Excessive salt consumption causes systemic calcium mishandling and worsens microarchitecture and strength of long bones in rats.
Tiyasatkulkovit Wacharaporn,Aksornthong Sirion,Adulyaritthikul Punyanuch,Upanan Pornpailin,Wongdee Kannikar,Aeimlapa Ratchaneevan,Teerapornpuntakit Jarinthorn,Rojviriya Catleya,Panupinthu Nattapon,Charoenphandhu Narattaphol
Excessive salt intake has been associated with the development of non-communicable diseases, including hypertension with several cardiovascular consequences. Although the detrimental effects of high salt on the skeleton have been reported, longitudinal assessment of calcium balance together with changes in bone microarchitecture and strength under salt loading has not been fully demonstrated. To address these unanswered issues, male Sprague-Dawley rats were fed normal salt diet (NSD; 0.8% NaCl) or high salt diet (HSD; 8% NaCl) for 5 months. Elevation of blood pressure, cardiac hypertrophy and glomerular deterioration were observed in HSD, thus validating the model. The balance studies were performed to monitor calcium input and output upon HSD challenge. The HSD-induced increase in calcium losses in urine and feces together with reduced fractional calcium absorption led to a decrease in calcium retention. With these calcium imbalances, we therefore examined microstructural changes of long bones of the hind limbs. Using the synchrotron radiation x-ray tomographic microscopy, we showed that trabecular structure of tibia and femur of HSD displayed a marked increase in porosity. Consistently, the volumetric micro-computed tomography also demonstrated a significant decrease in trabecular bone mineral density with expansion of endosteal perimeter in the tibia. Interestingly, bone histomorphometric analyses indicated that salt loading caused an increase in osteoclast number together with decreases in osteoblast number and osteoid volume. This uncoupling process of bone remodeling in HSD might underlie an accelerated bone loss and bone structural changes. In conclusion, long-term excessive salt consumption leads to impairment of skeletal mass and integrity possibly through negative calcium balance.
Piceatannol Exerts Anti-Obesity Effects in C57BL/6 Mice through Modulating Adipogenic Proteins and Gut Microbiota.
Tung Yen-Chen,Lin Yu-Hsuan,Chen Hong-Jhang,Chou Shen-Chieh,Cheng An-Chin,Kalyanam Nagabhushanam,Ho Chi-Tang,Pan Min-Hsiung
Molecules (Basel, Switzerland)
Obesity is a global health concern. Piceatannol (Pic), an analog of resveratrol (Res), has many reported biological activities. In this study, we investigated the anti-obesity effect of Pic in a high-fat diet (HFD)-induced obese animal model. The results showed that Pic significantly reduced mouse body weight in a dose-dependent manner without affecting food intake. Serum total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) levels, and blood glucose (GLU) were significantly lowered in Pic-treated groups. Pic significantly decreased the weight of liver, spleen, perigonadal and retroperitoneal fat compared with the HFD group. Pic significantly reduced the adipocyte cell size of perigonadal fat and decreased the weight of liver. Pic-treated mice showed higher phosphorylated adenosine 5'-monophosphate-activated protein kinase (pAMPK) and phosphorylated acetyl-CoA carboxylase (pACC) protein levels and decreased protein levels of CCAAT/enhancer-binding protein C/EBPα, peroxisome proliferator-activated receptor PPARγ and fatty acid synthase (FAS), resulting in decreased lipid accumulation in adipocytes and the liver. Pic altered the composition of the gut microbiota by increasing Firmicutes and and decreasing Bacteroidetes compared with the HFD group. Collectively, these results suggest that Pic may be a candidate for obesity treatment.
Recent advances and health implications of dietary fasting regimens on the gut microbiome.
Mohr Alex E,Gumpricht Eric,Sears Dorothy D,Sweazea Karen L
American journal of physiology. Gastrointestinal and liver physiology
Calorie restriction is a primary dietary intervention demonstrated over many decades in cellular and animal models to modulate aging pathways, positively affect age-associated diseases and, in clinical studies, to promote beneficial health outcomes. Because long-term compliance with daily calorie restriction has proven problematic in humans several intermittent fasting regimens, including alternate day fasting and time-restricted feeding, have evolved revealing similar clinical benefits as calorie restriction. Despite significant research on the cellular and physiological mechanisms contributing to, and responsible for, these observed benefits, relatively little research has investigated the impact of these various fasting protocols on the gut microbiome (GM). Reduced external nutrient supply to the gut may beneficially alter the composition and function of a "fed" gut microflora. Indeed, the prevalent, obesogenic Western diet can promote deleterious changes in the GM, signaling intermediates involved in lipid and glucose metabolism, and immune responses in the gastrointestinal tract. This review describes recent preclinical and clinical effects of varying fasting regimens on GM composition and associated physiology. Although the number of preclinical and clinical interventions are limited, significant data thus far suggest fasting interventions impact GM composition and physiology. However, there are considerable heterogeneities of study design, methodological considerations, and practical implications. Ongoing research on the health impact of fasting regimens on GM modulation is warranted.
Daily Eating Patterns and Their Impact on Health and Disease.
Zarrinpar Amir,Chaix Amandine,Panda Satchidananda
Trends in endocrinology and metabolism: TEM
Cyclical expression of cell-autonomous circadian clock components and key metabolic regulators coordinate often discordant and distant cellular processes for efficient metabolism. Perturbation of these cycles, either by genetic manipulation, disruption of light/dark cycles, or, most relevant to the human population, via eating patterns, contributes to obesity and dysmetabolism. Time-restricted feeding (TRF), during which time of access to food is restricted to a few hours, without caloric restriction, supports robust metabolic cycles and protects against nutritional challenges that predispose to obesity and dysmetabolism. The mechanism by which TRF imparts its benefits is not fully understood but likely involves entrainment of metabolically active organs through gut signaling. Understanding the relationship of feeding pattern and metabolism could yield novel therapies for the obesity pandemic.
Effectiveness of Intermittent Fasting and Time-Restricted Feeding Compared to Continuous Energy Restriction for Weight Loss.
Rynders Corey A,Thomas Elizabeth A,Zaman Adnin,Pan Zhaoxing,Catenacci Victoria A,Melanson Edward L
The current obesity epidemic is staggering in terms of its magnitude and public health impact. Current guidelines recommend continuous energy restriction (CER) along with a comprehensive lifestyle intervention as the cornerstone of obesity treatment, yet this approach produces modest weight loss on average. Recently, there has been increased interest in identifying alternative dietary weight loss strategies that involve restricting energy intake to certain periods of the day or prolonging the fasting interval between meals (i.e., intermittent energy restriction, IER). These strategies include intermittent fasting (IMF; >60% energy restriction on 2-3 days per week, or on alternate days) and time-restricted feeding (TRF; limiting the daily period of food intake to 8-10 h or less on most days of the week). Here, we summarize the current evidence for IER regimens as treatments for overweight and obesity. Specifically, we review randomized trials of ≥8 weeks in duration performed in adults with overweight or obesity (BMI ≥ 25 kg/m) in which an IER paradigm (IMF or TRF) was compared to CER, with the primary outcome being weight loss. Overall, the available evidence suggests that IER paradigms produce equivalent weight loss when compared to CER, with 9 out of 11 studies reviewed showing no differences between groups in weight or body fat loss.
Time-restricted feeding attenuates age-related cardiac decline in Drosophila.
Gill Shubhroz,Le Hiep D,Melkani Girish C,Panda Satchidananda
Science (New York, N.Y.)
Circadian clocks orchestrate periods of rest or activity and feeding or fasting over the course of a 24-hour day and maintain homeostasis. To assess whether a consolidated 24-hour cycle of feeding and fasting can sustain health, we explored the effect of time-restricted feeding (TRF; food access limited to daytime 12 hours every day) on neural, peripheral, and cardiovascular physiology in Drosophila melanogaster. We detected improved sleep, prevention of body weight gain, and deceleration of cardiac aging under TRF, even when caloric intake and activity were unchanged. We used temporal gene expression profiling and validation through classical genetics to identify the TCP-1 ring complex (TRiC) chaperonin, the mitochondrial electron transport chain complexes, and the circadian clock as pathways mediating the benefits of TRF.
Association between Time Restricted Feeding and Cognitive Status in Older Italian Adults.
Currenti Walter,Godos Justyna,Castellano Sabrina,Caruso Giuseppe,Ferri Raffaele,Caraci Filippo,Grosso Giuseppe,Galvano Fabio
BACKGROUND:Due to the increased life expectancy, the prevalence of aging-related health conditions, such as cognitive impairment, dementia and Alzheimer's disease is increasing. Among the modifiable risk factors, dietary factors have proved to be of primary importance in preserving and improving mental health and cognitive status in older adults, possibly through the modulation of adult neurogenesis, neuronal plasticity and brain signaling. Feeding/fasting timing manipulation has emerged as an innovative strategy to counteract and treat cognitive decline. The aim of this study was to investigate the association between the timing of the feeding period and cognitive status in a cross-sectional cohort of adults living in the Mediterranean area. METHODS:Demographic and dietary characteristics of 883 adults living in Southern Italy (Sicily) were analyzed. Food frequency questionnaires were used to calculate the time window between the first and the last meal of an average day. Participants with an eating time window duration of more than 10 h were then identified, as well as those with eating time restricted to less than 10 h (TRF). RESULTS:After adjusting for potential confounding factors, individuals adherent to TRF were less likely to have cognitive impairment, compared to those with no eating time restrictions [odds ratio (OR) = 0.28; 95% confidence intervals (CI): 0.07-0.90]; a similar association was found for individuals having breakfast (OR = 0.37, 95% CI: 0.16-0.89), but not for those having dinner. CONCLUSIONS:The results of this study reveal that time restricted eating may be positively associated with cognitive status, and thus exert plausible effects on brain health.
Time of Feeding Alters Obesity-Associated Parameters and Gut Bacterial Communities, but Not Fungal Populations, in C57BL/6 Male Mice.
van der Merwe Marie,Sharma Sunita,Caldwell Jade L,Smith Nicholas J,Gomes Charles K,Bloomer Richard J,Buddington Randal K,Pierre Joseph F
Current developments in nutrition
Background:Fasting and timed feeding strategies normalize obesity parameters even under high-fat dietary intake. Although previous work demonstrated that these dietary strategies reduce adiposity and improve metabolic health, limited work has examined intestinal microbial communities. Objectives:We determined whether timed feeding modifies the composition of the intestinal microbiome and mycobiome (yeast and fungi). Methods:Male C57BL/6 mice were fed a high-fat diet (HF) for 6 wk. Animals were then randomly assigned to the following groups ( = 8-10/group): ) HF ad libitum; ) purified high-fiber diet (Daniel Fast, DF); ) HF-time-restricted feeding (TRF) (6 h); ) HF-alternate-day fasting (ADF); or ) HF at 80% total caloric restriction (CR). After 8 wk, obesity and gut parameters were characterized. We also examined changes to the gut microbiome and mycobiome before, during, and following dietary interventions. Results:Body mass gain was reduced with all restricted dietary groups. HF-fed microbiota displayed lower α-diversity along with reduced phylum levels of and increased . Animals switched from HF to DF demonstrated a rapid transition in bacterial taxonomic composition, α-, and β-diversity that initially resembled HF, but was distinct after 4 and 8 wk of DF feeding. Time-or calorie-restricted HF-fed groups did not show changes at the phylum level, but α-diversity was increased, with specific genera altered. Six weeks of HF feeding reduced various fungal populations, particularly , , , and , and increased , , . However, 8 wk of intervention did not change the fungal populations, with the most abundant genera being , , and . Conclusions:These data suggest that timed-feeding protocols and diet composition do not significantly affect the gut fungal community, despite inducing measurable shifts in the bacterial population that coincide with improvements in metabolism.
Safety of 8-h time restricted feeding in adults with obesity.
Gabel Kelsey,Hoddy Kristin K,Varady Krista A
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
This study examines the safety of time restricted feeding (TRF; 8-h feeding window/16-h fasting window daily) in obese adults. Twenty-three subjects participated in an 8-h TRF intervention for 12 weeks. Self-reported adverse events, body image perception, complete blood count, and disordered eating patterns did not change from baseline to week 12. These findings suggest that consuming food within an 8-h window can safely facilitate weight loss in subjects with obesity.
Effect of a Six-Week Intermittent Fasting Intervention Program on the Composition of the Human Body in Women over 60 Years of Age.
Domaszewski Przemysław,Konieczny Mariusz,Pakosz Paweł,Bączkowicz Dawid,Sadowska-Krępa Ewa
International journal of environmental research and public health
The objective of this research was to determine the effectiveness of intermittent fasting (IF) in reducing body fat and lowering body mass index. An additional objective was to determine the feasibility of applying IF in overweight women over 60 years of age, which was assessed by the ratio of subjects who resigned from the diet plan. This study included a group of 45 women over 60 years of age. The intervention in the experimental group involved complete abstinence from food intake for 16 h per day, from 20:00 p.m. to 12:00 a.m. (the next day). The results demonstrated that the body weight in the subjects in the experimental group (EXP) group decreased by almost 2 kg and this decrease was visible in the remaining parameters related to body fat mass. The skeletal muscle mass did not change significantly, which indicates an actual decrease in the fat mass. The proportion of subjects who did not succeed in following the prescribed diet plan was 12%. The application of intermittent fasting in female subjects over 60 years of age resulted in positive changes in body composition. Time-restricted feeding (TRF) was characterized by a lower resignation rate compared to other diets involving intermittent fasting.
Nutrition and the circadian system.
Potter Gregory D M,Cade Janet E,Grant Peter J,Hardie Laura J
The British journal of nutrition
The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases.
The Effects of Time Restricted Feeding on Overweight, Older Adults: A Pilot Study.
Anton Stephen D,Lee Stephanie A,Donahoo William T,McLaren Christian,Manini Todd,Leeuwenburgh Christiaan,Pahor Marco
A growing body of evidence indicates that time restricted feeding (TRF), a popular form of intermittent fasting, can activate similar biological pathways as caloric restriction, the only intervention consistently found to extend healthy lifespan in a variety of species. Thus, TRF may have the potential to also improve function in older adults. Given the challenges many individuals have in following calorie restriction regimens over long-time periods, evaluation of alternative approaches that may produce weight loss and improve function in overweight, older adults is important. Ten overweight, sedentary older adults (≥65 years) at risk for, or with mobility impairments, defined by slow gait speed (<1.0 m/s) participated in this trial. All participants received the intervention and were instructed to fast for approximately 16 h per day over the entire four-week intervention. Outcomes included changes in body weight, waist circumference, cognitive and physical function, health-related quality of life, and adverse events. Adherence levels were high (mean = 84%) based on days goal was met, and mean weight loss was 2.6 kg ( < 0.01). Since body composition was not measured in this study, it is unclear if the observed weight loss was due to loss of fat mass, muscle mass, or the combination of fat and muscle mass. There were no significant changes in other outcomes; however, there were clinically meaningful changes in walking speed and improvements in quality of life, with few reported adverse events. The findings of this pilot study suggest that time restricted feeding is an acceptable and feasible eating pattern for overweight, sedentary older adults to follow.
Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms.
Hwangbo Dae-Sung,Lee Hye-Yeon,Abozaid Leen Suleiman,Min Kyung-Jin
Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.
Impact of intermittent fasting on health and disease processes.
Mattson Mark P,Longo Valter D,Harvie Michelle
Ageing research reviews
Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16-48h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer's disease Parkinson's disease and stroke. Studies of IF (e.g., 60% energy restriction on 2days per week or every other day), PF (e.g., a 5day diet providing 750-1100kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.
Effect of 8-h time-restricted feeding on sleep quality and duration in adults with obesity.
Gabel Kelsey,Hoddy Kristin K,Burgess Helen J,Varady Krista A
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
This study examined the effects of time-restricted feeding (TRF; 8-h feeding window/16-h fasting window daily) on sleep. Obese adults ( = 23) followed 8-h TRF for 12 weeks. Pittsburgh Sleep Quality Index (PSQI) total score was below 5 at week 1 (4.7 ± 0.5) and week 12 (4.8 ± 0.7), indicating good sleep quality throughout the trial. Subjective measures of wake time, bedtime, and sleep duration remained unchanged. Findings from this secondary analysis indicate that TRF does not alter sleep quality or duration in subjects with obesity. This study is the first to show that TRF (8-h feeding window/16-h fasting window daily) does not alter sleep quality or duration in subjects with obesity.
Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan.
Longo Valter D,Panda Satchidananda
Most animals alternate periods of feeding with periods of fasting often coinciding with sleep. Upon >24 hr of fasting, humans, rodents, and other mammals enter alternative metabolic phases, which rely less on glucose and more on ketone body-like carbon sources. Both intermittent and periodic fasting result in benefits ranging from the prevention to the enhanced treatment of diseases. Similarly, time-restricted feeding (TRF), in which food consumption is restricted to certain hours of the day, allows the daily fasting period to last >12 hr, thus imparting pleiotropic benefits. Understanding the mechanistic link between nutrients and the fasting benefits is leading to the identification of fasting-mimicking diets (FMDs) that achieve changes similar to those caused by fasting. Given the pleiotropic and sustained benefits of TRF and FMDs, both basic science and translational research are warranted to develop fasting-associated interventions into feasible, effective, and inexpensive treatments with the potential to improve healthspan.
Influence of a Mediterranean Dietary Pattern on Body Fat Distribution: Results of the PREDIMED-Canarias Intervention Randomized Trial.
Álvarez-Pérez Jacqueline,Sánchez-Villegas Almudena,Díaz-Benítez Elena María,Ruano-Rodríguez Cristina,Corella Dolores,Martínez-González Míguel Ángel,Estruch Ramón,Salas-Salvadó Jordi,Serra-Majem Lluís,
Journal of the American College of Nutrition
OBJECTIVE:To assess the influence of a Mediterranean dietary pattern (MeDiet) on anthropometric and body composition parameters in one of the centers of the PREDIMED randomized dietary trial. SUBJECTS/SETTINGS:351 Canarian free-living subjects aged 55 to 80 years, with type 2 diabetes or ≥3 cardiovascular risk factors. INTERVENTION:Participants were randomly assigned to one of 3 different dietary interventions: MeDiet + extra-virgin olive oil (EVOO), MeDiet + nuts (walnuts, almonds, and hazelnuts), or a control low-fat diet. Total energy intake was ad libitum. OUTCOME MEASURES:Measures included changes in anthropometric measures (weight, body mass index [BMI] and waist circumference [WC]), body fat distribution, energy, and nutrient intake after 1 year. Body composition (percentage of total body fat [%TBF], total fat mass [TFM], free fat mass [FFM], percentage of truncal fat [%TrF], truncal fat mass [TrFM]) and total body water (TBW) were estimated by octapolar electrical impedance analysis. STATISTICAL ANALYSES:Paired t tests were conducted to assess within-group changes. Analyses of variance (ANOVAs) were used to assess the effect of the dietary intervention on the percentage change in anthropometric variables, body composition, and dietary intake profile. All pairwise comparisons that were statistically significant in ANOVA were subsequently adjusted using the Benjamini-Hochberg test, which penalizes for multiple comparisons. RESULTS:After 1 year of intervention, significant within-group reductions in all anthropometric variables were observed for the MeDiet + EVOO and the control group. The MeDiet + nuts group exhibited a significant reduction in WC and TBW. The control group showed a significant increase in %TBF and a reduction in TBW. The control group showed a significant increase in the percentage of total body fat and a reduction in TBW. However, we did not find any between-group significant difference in anthropometric or body composition changes. CONCLUSIONS:Mediterranean diets enriched with EVOO or specific mixed nuts (walnuts, almonds, hazelnuts) that contain approximately 40% total fat can be alternative options to low-fat diets for weight maintenance regimes in older overweight or obese adults.
Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock.
Chaix Amandine,Lin Terry,Le Hiep D,Chang Max W,Panda Satchidananda
Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects. However, when fed the same diet under TRF (food access restricted to 10 hr during the dark phase) they were protected from excessive weight gain and metabolic diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation of hepatic lipids and enhanced cellular defenses against metabolic stress. These results suggest that the circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding and fasting and by maintaining balance between nutrient and cellular stress responses.
Time-restricted feeding and risk of metabolic disease: a review of human and animal studies.
Rothschild Jeff,Hoddy Kristin K,Jambazian Pera,Varady Krista A
Time-restricted feeding (TRF), a key component of intermittent fasting regimens, has gained considerable attention in recent years. TRF allows ad libitum energy intake within controlled time frames, generally a 3-12 hour range each day. The impact of various TRF regimens on indicators of metabolic disease risk has yet to be investigated. Accordingly, the objective of this review was to summarize the current literature on the effects of TRF on body weight and markers of metabolic disease risk (i.e., lipid, glucoregulatory, and inflammatory factors) in animals and humans. Results from animal studies show TRF to be associated with reductions in body weight, total cholesterol, and concentrations of triglycerides, glucose, insulin, interleukin 6, and tumor necrosis factor-α as well as with improvements in insulin sensitivity. Human data support the findings of animal studies and demonstrate decreased body weight (though not consistently), lower concentrations of triglycerides, glucose, and low-density lipoprotein cholesterol, and increased concentrations of high-density lipoprotein cholesterol. These preliminary findings show promise for the use of TRF in modulating a variety of metabolic disease risk factors.
Response of peripheral rhythms to the timing of food intake.
Hatori Megumi,Panda Satchidananda
Methods in enzymology
Metabolism and physiology in animals show diurnal rhythm to adapt to the daily cycles of activity-rest and the associated rhythm in feeding and fasting. Accordingly, gene expression, protein activities, and numerous metabolites show daily rhythm in abundance. The significance of these rhythms in promoting healthy lifespan and preventing disease has recently come to light. Mice with genetic disruption of circadian rhythm, mice, and humans under shift-work paradigm, and mice fed high-fat diet ad libitum exhibit chronic disruption of feeding-fasting rhythm and dampened daily rhythms in physiology, metabolism, and gene expression. These dampened rhythms are associated with metabolic diseases. Conversely, time-restricted feeding, in which mice are fed for certain number of hours every day, restores rhythms and can prevent obesity and metabolic diseases even when mice are fed high-fat diet. These observations seek mechanistic explanations, which will require careful experiments in which feeding duration, genotype, nutrient, and feeding time relative to light:dark cycle will be manipulated and molecular changes in peripheral organs and a few brain regions will be assessed. This chapter will primarily focus on the use of mouse as an experimental animal and the experimental setup so that the molecular readouts can be better interpreted.
Circadian-based Treatment Strategy Effective in the BACHD Mouse Model of Huntington's Disease.
Whittaker Daniel S,Loh Dawn H,Wang Huei-Bin,Tahara Yu,Kuljis Dika,Cutler Tamara,Ghiani Cristina A,Shibata Shigenobu,Block Gene D,Colwell Christopher S
Journal of biological rhythms
Huntington's disease (HD) patients suffer from progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep-wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and excessive fatigue. The BACHD mouse model exhibits many HD core symptoms including circadian dysfunction. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early interventions that improve circadian rhythmicity could benefit HD symptoms and delay disease progression. We evaluated the effects of time-restricted feeding (TRF) on the BACHD mouse model. At 3 months of age, the animals were divided into 2 groups: ad lib and TRF. The TRF-treated BACHD mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle (ZT 15-21) of the period when mice are normally active (ZT 12-24). Following 3 months of treatment (when mice reached the early disease stage), the TRF-treated BACHD mice showed improvements in their locomotor activity and sleep behavioral rhythms. Furthermore, we found improved heart rate variability, suggesting that their autonomic nervous system dysfunction was improved. On a molecular level, TRF altered the phase but not the amplitude of the PER2::LUC rhythms measured in vivo and in vitro. Importantly, treated BACHD mice exhibited improved motor performance compared with untreated BACHD controls, and the motor improvements were correlated with improved circadian output. It is worth emphasizing that HD is a genetically caused disease with no known cure. Lifestyle changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of circadian-based treatment strategies in a preclinical model of HD.
The effects of time-restricted feeding on lipid metabolism and adiposity.
Chaix Amandine,Zarrinpar Amir
Maintaining natural feeding rhythms with time-restricted feeding (TRF), without altering nutritional intake, prevents and reverses diet-induced obesity (DIO) and its associated metabolic disorders in mice. TRF has a direct effect on animal adiposity, causes an alteration of adipokine signaling, and diminishes white adipose tissue inflammation. Many genes involved in lipid metabolism are normally circadian, but their expression is perturbed with DIO; TRF restores their cyclical expression. One mechanism through which TRF could affect host metabolism is by altering the gut microbiome. Changes in the gut microbiome are coupled with an altered stool bile acid profile. Hence, TRF could affect lipid metabolism by altering bile acid signaling. TRF introduces many new possibilities in treating obesity and its associated metabolic disorders. However, further studies are needed to show whether these physiological findings in mice translate to humans.
Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.
Wang Huei-Bin,Loh Dawn H,Whittaker Daniel S,Cutler Tamara,Howland David,Colwell Christopher S
Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays.
Effects of time-restricted feeding on body weight, body composition and vital signs in low-income women with obesity: A 12-month randomized clinical trial.
de Oliveira Maranhão Pureza Isabele Rejane,da Silva Junior André Eduardo,Silva Praxedes Dafiny Rodrigues,Lessa Vasconcelos Laís Gomes,de Lima Macena Mateus,Vieira de Melo Ingrid Sofia,de Menezes Toledo Florêncio Telma Maria,Bueno Nassib Bezerra
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Time-restricted feeding (TRF) studies usually are of short-term, involving heterogeneous populations, without a control group with similar energy restriction. Besides, it seldom assess vital signs such as body temperature and heart rate, which may be influenced by the fasting state. In this investigation, we assessed the long-term effects of TRF on body weight, body composition and vital signs of low-income women with obesity undergoing diets with the same energy deficit. METHODS:Low-income women with obesity were randomly allocated to a group with a hypoenergetic diet and 12 h of TRF or to a group with only a hypoenergetic diet, for 12 months. Body fat and waist circumference were estimated using a tetrapolar electrical bioimpedance and an inelastic measuring tape, respectively, at baseline and after 4, 6 and 12 months of intervention. Systolic and diastolic blood pressure, heart rate, and axillary temperature were measured at baseline and 12 months of intervention. The energy content of the diets was determined based on the women's resting metabolic rate (by indirect calorimetry) and level of physical activity (by triaxial accelerometers). Effects were analyzed using an intention-to-treat approach. RESULTS:Fifty-eight women were randomized and 31 (53.44%) were lost to follow-up at 12 months. Dropout rates were similar between groups. In the intention-to-treat analysis, there were no significant changes in the body weight after 12 months (Differences in changes from baseline between groups: -0.05 95%CI [-2.34; 2.24] Kg; p = 0.96). An increase in axillary temperature (0.40 °C, 95% CI [-0.14; 0.67]°C, p < 0.01), a reduction in the percentage of body fat (-1.64%, 95% CI [-3.08; -0.19]%, p = 0.02) and waist circumference (-2.57 cm, 95% CI [-5.73; 0.58] cm, p = 0.03 in the mixed model involving 4 measurements) were observed in the intervention group, when compared to the control group. CONCLUSIONS:TRF showed no effects on weight loss. Nevertheless the findings on waist circumference and body fat, although not clinically meaningful, suggest that this strategy may help in the long-term management of obesity in this population, since it is an easy to apply intervention. Axillary temperature findings warrants further investigation. Registered under www.ensaiosclinicos.gov.br Identifier no. RBR-387v6v. TRIAL REGISTRATION:http://www.ensaiosclinicos.gov.br/rg/RBR-387v6v/.
Food hardness influences the progression of age-related hearing loss in mice.
Oike Hideaki,Kohyama Kaoru,Mochizuki-Kawai Hiroko,Azami Kayo
C57BL/6J and DBA/2J mice are often used for hearing research because of their early onset and progression of age-related hearing loss (AHL). Here, we report that the hardness of the diet affects the progression of AHL in these mice. When C57BL/6J mice and DBA/2J mice were fed a pellet-type or powder-type standard AIN93M diet, the pellet diet significantly promoted AHL. AHL promotion was eliminated by crushing the pellet diet to a powder. Subsequently, when C57BL/6J mice were fed the pellet-type AIN93M diet obtained from three different manufacturers, two of them significantly promoted AHL. The hardness of the diets was measured, and it was found that the two diets that promoted AHL were significantly harder than the other diet. Next, we attempted to reduce diet hardness by replacing some nutritional ingredients with dried eggs or phosphatidylcholine (PC), and we succeeded in obtaining brittle diets with lower hardness values. Then, C57BL/6J mice were bred with brittle diets for 6 months and the promotion of AHL was suppressed to the equivalent level as the powder diet. Furthermore, when senescence-accelerated mice, SAMP8, were fed a brittle diet for one year, the progression of AHL was also suppressed; however, it did not affect other aging indexes, such as mental and physical performance. We also confirmed that a high-fat pellet diet, which is soft even in pellet form, did not promote AHL. Time-restricted feeding (tRF), which is a chrono-nutritional method to delay aging, ameliorated the promotion of AHL by the hard AIN93M pellets in C57BL/6J mice. These results indicate that the physical form and hardness of diets affect the progression of AHL in mouse models.
Four Weeks of Time-Restricted Feeding Combined with Resistance Training Does Not Differentially Influence Measures of Body Composition, Muscle Performance, Resting Energy Expenditure, and Blood Biomarkers.
Stratton Matthew T,Tinsley Grant M,Alesi Michaela G,Hester Garrett M,Olmos Alex A,Serafini Paul R,Modjeski Andrew S,Mangine Gerald T,King Kelsey,Savage Shelby N,Webb Austin T,VanDusseldorp Trisha A
Recently, interest in time-restricted feeding (TRF) has increased from reports highlighting improvements in body composition and muscular performance measures. Twenty-six recreationally active males were randomly assigned to either TRF ( = 13; ~22.9 years; 82.0 kg; 178.1 cm; 8 h eating window, 25% caloric deficit, 1.8 g/kg/day protein) or normal diet (ND; = 13; ~22.5 years; 83.3 kg; 177.5 cm; normal meal pattern; 25% caloric deficit, 1.8 g/kg/day protein) groups. Participants underwent 4-weeks of supervised full body resistance training. Changes in body composition (fat mass (FM), fat free mass (FFM), and body fat percentage (BF%)), skeletal muscle cross sectional area (CSA) and muscle thickness (MT) of the vastus lateralis (VL), rectus femoris, (RF), and biceps brachii (BB) muscles, resting energy expenditure (REE), muscular performance, blood biomarkers, and psychometric parameters were assessed. Significant ( < 0.05) decreases were noted in BM, FM, BF%, testosterone, adiponectin, and REE, along with significant increases in BP, LP, VJ, VJ, VL, BB, and BB in both groups. Plasma cortisol levels were significantly elevated at post ( = 0.018) only in ND. Additionally, FFM was maintained equally between groups. Thus, a TRF style of eating does not enhance reductions in FM over caloric restriction alone during a 4-week hypocaloric diet.
Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults.
Martens Christopher R,Rossman Matthew J,Mazzo Melissa R,Jankowski Lindsey R,Nagy Erzsebet E,Denman Blair A,Richey James J,Johnson Sarah A,Ziemba Brian P,Wang Yang,Peterson Courtney M,Chonchol Michel,Seals Douglas R
Chronic calorie restriction (CR) improves cardiovascular function and several other physiological markers of healthspan. However, CR is impractical in non-obese older humans due to potential loss of lean mass and bone density, poor adherence, and risk of malnutrition. Time-restricted feeding (TRF), which limits the daily feeding period without requiring a reduction in calorie intake, may be a promising alternative healthspan-extending strategy for midlife and older adults; however, there is limited evidence for its feasibility and efficacy in humans. We conducted a randomized, controlled pilot study to assess the safety, tolerability, and overall feasibility of short-term TRF (eating <8 h day for 6 weeks) without weight loss in healthy non-obese midlife and older adults, while gaining initial insight into potential efficacy for improving cardiovascular function and other indicators of healthspan. TRF was safe and well-tolerated, associated with excellent adherence and reduced hunger, and did not influence lean mass, bone density, or nutrient intake. Cardiovascular function was not enhanced by short-term TRF in this healthy cohort, but functional (endurance) capacity and glucose tolerance were modestly improved. These results provide a foundation for conducting larger clinical studies of TRF in midlife and older adults, including trials with a longer treatment duration.
Time-restricted feeding improves the reproductive function of female mice via liver fibroblast growth factor 21.
Hua Lun,Feng Bin,Huang Liansu,Li Jing,Luo Ting,Jiang Xuemei,Han Xingfa,Che Lianqiang,Xu Shengyu,Lin Yan,Fang Zhengfeng,Wu De,Zhuo Yong
Clinical and translational medicine
BACKGROUND:There has been a significant increase, to epidemic levels, of obese and overweight women of reproductive age, causing impairments to reproductive health. Time-restricted feeding (TRF) including isocaloric intake has shown to be preventive of obesity-related disorders. However, its therapeutic ability to improve the reproductive function of female remains largely unknown. METHODS:Here, we investigated the ability of TRF to improve the reproductive function in wild-type and liver-specific FGF21 knockout female mice. To study fertility, a continuous and a short-term fertility test, gonadotropin releasing-hormone (GnRH), and Kisspeptin test were performed. Immortalized GnRH neuron was used to examine the direct role of liver fibroblast growth factor 21 (FGF21) on GnRH secretion. RESULTS:We found that TRF rescues female mice from bodyweight gain and glucose intolerance, as well as ovarian follicle loss and dysfunction of estrus cyclicity induced by high-fat diet. Furthermore, the beneficial effects of the TRF regimen on the reproductive performance were also observed in mice fed both chow and high-fat diet. However, those beneficial effects of TRF on metabolism and reproduction were absent in liver-specific FGF21 knockout mice. In vitro, FGF21 directly acted on GnRH neurons to modulate GnRH secretion via extracellular regulated protein kinases (ERK ) pathway. CONCLUSIONS:Overall, time-restricted feeding improves the reproductive function of female mice and liver FGF21 signaling plays a key role in GnRH neuron activity in female mice.
Time-restricted feeding causes irreversible metabolic disorders and gut microbiota shift in pediatric mice.
Hu Dandan,Mao Yilei,Xu Gang,Liao Wenjun,Ren Jinjun,Yang Huayu,Yang Jun,Sun Lejia,Chen Hongyu,Wang Wenda,Wang Yanan,Sang Xinting,Lu Xin,Zhang Hongbing,Zhong Shouxian
BACKGROUND:Time-restricted feeding regimen (TRF), that is, no food consumption for 14-16 h during the light phase per day, attenuates the fattening traits and metabolic disorders in adults. This study aims to further investigate whether TRF would be protective against similar nutritional challenges in juvenile mice. METHODS:Mice in the experimental group were treated with TRF during the first 4 weeks (considered to be the childhood phase of mice) before switching to ad libitum (AD) feeding pattern as adults; the control group with all subjects sticks to AD mode. Body weight was monitored, and serum biochemistry, sexual maturity, immune function, and gut microbiota were assessed at a certain timing. RESULTS:Mice treated with TRF during the childhood period (from weaning age) but went through AD feeding pattern as adults demonstrated the tendency of higher body weight, higher levels of serum glucose, shrunken Langerhans islets, fatty liver disease, thickening of aortic walls, delayed sexual development, increased proportion of T regulatory cells, and unhealthy gut microbiota. CONCLUSION:Childhood TRF causes pleiotropic adverse effects, including severe irreversible metabolic disorders, depressed immune function, and retarded puberty. Microbiota set the stage for TRF to employ downstream reactions on the above changes.
Effects of 4- and 6-h Time-Restricted Feeding on Weight and Cardiometabolic Health: A Randomized Controlled Trial in Adults with Obesity.
Cienfuegos Sofia,Gabel Kelsey,Kalam Faiza,Ezpeleta Mark,Wiseman Eric,Pavlou Vasiliki,Lin Shuhao,Oliveira Manoela Lima,Varady Krista A
Time-restricted feeding (TRF) regimens have grown in popularity; however, very few studies have examined their weight-loss efficacy. We conducted the first human trial (Clinicaltrials.gov NCT03867773) to compare the effects of two popular forms of TRF (4 and 6 h) on body weight and cardiometabolic risk factors. Adults with obesity were randomized to 4-h TRF (eating only between 3 and 7 p.m.), 6-h TRF (eating only between 1 and 7 p.m.), or a control group (no meal timing restrictions). After 8 weeks, 4- and 6-h TRF produced comparable reductions in body weight (∼3%), insulin resistance, and oxidative stress, versus controls. Energy intake was reduced by ∼550 kcal/day in both TRF groups, without calorie counting. These findings suggest that 4- and 6-h TRF induce mild reductions in body weight over 8 weeks and show promise as interventions for weight loss. These diets may also improve some aspects of cardiometabolic health.
Combined virgin coconut oil and tocotrienol-rich fraction protects against bone loss in osteoporotic rat model.
Malik Mohd Maaruf Abdul,Othman Faizah,Hussan Farida,Shuid Ahmad Nazrun,Saad Qodriyah Mohd
Background and Aim:Both virgin coconut oil (VCO) and tocotrienol-rich fraction (TRF) are rich in antioxidants and may protect the bone against bone loss induced by ovariectomy and high-fat diet. The study aimed to determine the protective effects of combined therapy of VCO and TRF on osteoporosis in ovariectomized (OVX) rat fed with high-fat diet. Materials and Methods:Thirty-six female Sprague-Dawley rats were divided into six groups: Sham-operated (SHAM), OVX control, OVX and given Premarin at 64.5 µg/kg (OVX+E2), OVX and given VCO at 4.29 ml/kg (OVX+V), OVX and given TRF at 30 mg/kg (OVX+T), and OVX and given a combination of VCO at 4.29 ml/kg and TRF at 30 mg/kg (OVX+VT). Following 24 weeks of treatments, blood and femora samples were taken for analyses. Results:There were no significant differences in serum osteocalcin levels between the groups (p>0.05), while serum C-terminal telopeptide of Type I collagen levels of the OVX+VT group were significantly lower than the other groups (p<0.05). The dynamic bone histomorphometry analysis of the femur showed that the double-labeled surface/bone surface (dLS/BS), mineral apposition rate, and bone formation rate/BS of the OVX+E2, OVX+T, and OVX+VT groups were significantly higher than the rest of the groups (p<0.05). Conclusion:A combination of VCO and TRF has the potential as a therapeutic agent to restore bone loss induced by ovariectomy and high-fat diet.
A Comparison of Dietary and Caloric Restriction Models on Body Composition, Physical Performance, and Metabolic Health in Young Mice.
Smith Nicholas Jg,Caldwell Jade L,van der Merwe Marie,Sharma Sunita,Butawan Matthew,Puppa Melissa,Bloomer Richard J
Time-restricted feeding (TRF), alternate day fasting (ADF), and the dietary restriction model known as the Daniel Fast (DF; a vegan/non-processed food diet plan) have garnered attention recently as nutritional interventions to combat obesity. We compared the effects of various dietary models on body composition, physical performance, and metabolic health in C57BL/6 mice. Sixty young C57BL/6 male mice were assigned a diet of TRF, ADF, DF, caloric restriction (CR), a high-fat Western diet (HF) fed , or standard rodent chow for eight weeks. Their body composition, run time to exhaustion, fasting glucose, insulin, and glucose tolerance test area under the glucose curve (AUC) were determined. Compared to the HF group, all groups displayed significantly less weight and fat mass gain, as well as non-significant changes in fat-free mass. Additionally, although not statistically significant, all groups displayed greater run time to exhaustion relative to the HF group. Compared to the HF group, all groups demonstrated significantly lower fasting glucose, insulin, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as well as improved glucose tolerance, and the ADF group displayed the best fasting glucose and glucose tolerance results, with DF having the best HOMA-IR. All investigated fasting protocols may improve body composition, measures of insulin sensitivity, and physical performance compared to a high-fat Western diet. The DF and ADF protocols are most favorable with regards to insulin sensitivity and glucose tolerance. Since our selected dietary protocols have also been investigated in humans with success, it is plausible to consider that these dietary models could prove beneficial to men and women seeking improved body composition and metabolic health.
Palm tocotrienol-rich fraction improves vascular proatherosclerotic changes in hyperhomocysteinemic rats.
Norsidah Ku-Zaifah,Asmadi Ahmad Yusof,Azizi Ayob,Faizah Othman,Kamisah Yusof
Evidence-based complementary and alternative medicine : eCAM
This study investigated the effects of palm tocotrienol-rich fraction (TRF) on aortic proatherosclerotic changes in rats fed with a high methionine diet. Forty-two male Wistar rats were divided into six groups. The first group was the control (fed with a basal diet). Another five groups were fed with 1% methionine diet for 10 weeks. From week 6 onward, folate (8 mg/kg diet) or palm TRF (30, 60, and 150 mg/kg diets) was added into the diet of the last four rat groups, respectively. The high methionine diet raised the plasma total homocysteine and aortic lipid peroxidation, which were reduced by the palm TRF and folate supplementations. Plasma nitric oxide was reduced in the high methionine group compared to the control (3.72 ± 0.57 versus 6.65 ± 0.53 μ mol/L, P < 0.05), which reduction was reversed by the palm TRF (60 and 150 mg/kg) and folate supplementations. The increased aortic vascular cell adhesion molecule-1 expression in the methionine group (2.58 ± 0.29) was significantly reduced by the folate (1.38 ± 0.18) and palm TRF at 150 mg/kg (1.19 ± 0.23). Palm TRF was comparable to folate in reducing high methionine diet-induced plasma hyperhomocysteinemia, aortic oxidative stress, and inflammatory changes in rats.
Adherence to Time-Restricted Feeding and Impact on Abdominal Obesity in Primary Care Patients: Results of a Pilot Study in a Pre-Post Design.
Kesztyüs Dorothea,Cermak Petra,Gulich Markus,Kesztyüs Tibor
The epidemic of lifestyle-dependent diseases and the failure of previous interventions to combat the main causes demand an alternative approach. Abdominal obesity is associated with most of these diseases and is a good target for therapeutic and preventive measures. Time-restricted feeding (TRF) offers a low-threshold, easy-to-implement lifestyle-modification concept with promising results from animal testing. Here, we describe a pilot study of TRF with abdominally obese participants (waist-to-height ratio, WHtR ≥0.5) in a general practitioner's office. Participants ( = 40, aged 49.1 ± 12.4, 31 females) were asked to restrict their daily eating time to 8-9 hours in order to prolong their overnight fasting period to 15-16 hours. Questionnaires, anthropometrics, and blood samples were used at baseline and at follow-up. After three months of TRF, participants had reached the fasting target, on average, on 85.5 ± 15.2% of all days recorded. Waist circumference (WC) was reduced by -5.3 ± 3.1cm ( < 0.001), and three participants reached a WHtR <0.5. HbA1c was diminished by -1.4 ± 3.5 mmol/mol ( = 0.003). TRF may be an easily understandable and readily adoptable lifestyle change with the potential to reduce abdominal obesity and lower the risk for cardiometabolic diseases. Further well-designed studies are necessary to investigate the applicability and usefulness of TRF for public health.
Limiting feeding to the active phase reduces blood pressure without the necessity of caloric reduction or fat mass loss.
Cote Isabelle,Toklu Hale Z,Green Sara M,Morgan Drake,Carter Christy S,Tümer Nihal,Scarpace Philip J
American journal of physiology. Regulatory, integrative and comparative physiology
Reducing body weight has been shown to lower blood pressure in obesity-related hypertension. However, success of those lifestyle interventions is limited due to poor long-term compliance. Emerging evidence indicates that feeding schedule plays a role on the regulation of blood pressure. With two studies, we examined the role of feeding schedule on energy homeostasis and blood pressure. In study 1, rats were fed a high-fat diet (HFD) ad libitum for 24 h (Control) or for 12 h during the dark phase (time-restricted feeding, TRF). In study 2, rats fed a HFD were administered a long-acting α-MSH analog at either light onset [melanotan II (MTII) light] or dark onset (MTII dark) or saline (Control). MTII light animals ate most of their calories during the active phase, similar to the TRF group. In study 1, Control and TRF rats consumed the same amount of food and gained the same amount of weight and fat mass. Interestingly, systolic and mean arterial pressure (MAP) was lower in the TRF group. In study 2, food intake was significantly lower in both MTII groups relative to Control. Although timing of injection affected light versus dark phase food consumption, neither body weight nor fat mass differed between MTII groups. Consistent with study 1, rats consuming their calories during the active phase displayed lower MAP. These data indicate that limiting feeding to the active phase reduces blood pressure without the necessity of reducing calories or fat mass, which could be relevant to obesity-related hypertension.
Eight-hour time-restricted feeding improves endocrine and metabolic profiles in women with anovulatory polycystic ovary syndrome.
Li Chunzhu,Xing Chuan,Zhang Jiaqi,Zhao Han,Shi Wenjing,He Bing
Journal of translational medicine
BACKGROUND:Time-restricted feeding (TRF) is a form of intermittent fasting, which is beneficial for weight loss and cardiometabolic health. Polycystic ovary syndrome (PCOS) is one of the most common reproductive endocrine and metabolic diseases affecting women of childbearing age. It is associated with an increased prevalence of metabolic syndrome, cardiovascular diseases and type 2 diabetes. The effects of TRF on PCOS patients remains undefined, here we investigated the impact of TRF on women with anovulatory PCOS. METHODS:Eighteen PCOS women aged between 18 and 31 with anovulation participated in a 6-week trial which were divided into two consecutive periods: (1) 1-week baseline weight stabilization period and (2) 5-week TRF period. Fifteen participants completed the study. Changes in body weight, body mass index (BMI), Waist-to-Hip Ratio, skeletal muscle mass, body fat mass (BFM), body fat percentage (BF%), visceral fat area (VFA), luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH, total testosterone (TT), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting glucose, fasting insulin (FINS), homeostasis model assessment-insulin resistance (HOMA-IR), area under the curve (AUC) for insulin (AUCIns), area under the curve (AUC) for glucose (AUCGlu), AUCIns/AUCGlu Ratio, lipids, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase, high-sensitivity C-reactive protein (hsCRP), insulin-like growth factor (IGF-1), menstrual cycle and eating behaviors were evaluated. RESULTS:Significant changes in body weight, BMI, BFM, BF%, VFA, TT, SHBG, FAI, FINS, HOMA-IR, AUCIns, AUCIns/AUCGlu Ratio, ALT, hsCRP and IGF-1 were found after the TRF period. An improvement in menstrual cycle irregularity was detected in 73.3% (11/15) patients. CONCLUSION:The diet of TRF may be beneficial to anovulatory PCOS on weight loss especially reducing body fat, improving menstruation, hyperandrogenemia, insulin resistance and chronic inflammation. Trial registration Clinicaltrial.gov, NCT04580433, registered October 8, 2020, https://clinicaltrials.gov/ct2/show/NCT04580433.
Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption.
Villanueva Jesús E,Livelo Christopher,Trujillo Adriana S,Chandran Sahaana,Woodworth Brendon,Andrade Leo,Le Hiep D,Manor Uri,Panda Satchidananda,Melkani Girish C
Pathological obesity can result from genetic predisposition, obesogenic diet, and circadian rhythm disruption. Obesity compromises function of muscle, which accounts for a majority of body mass. Behavioral intervention that can counteract obesity arising from genetic, diet or circadian disruption and can improve muscle function holds untapped potential to combat the obesity epidemic. Here we show that Drosophila melanogaster (fruit fly) subject to obesogenic challenges exhibits metabolic disease phenotypes in skeletal muscle; sarcomere disorganization, mitochondrial deformation, upregulation of Phospho-AKT level, aberrant intramuscular lipid infiltration, and insulin resistance. Imposing time-restricted feeding (TRF) paradigm in which flies were fed for 12 h during the day counteracts obesity-induced dysmetabolism and improves muscle performance by suppressing intramuscular fat deposits, Phospho-AKT level, mitochondrial aberrations, and markers of insulin resistance. Importantly, TRF was effective even in an irregular lighting schedule mimicking shiftwork. Hence, TRF is an effective dietary intervention for combating metabolic dysfunction arising from multiple causes.
Hypothalamic leptin sensitivity and health benefits of time-restricted feeding are dependent on the time of day in male mice.
Boucsein Alisa,Rizwan Mohammed Z,Tups Alexander
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Synchronization between biologic clocks and metabolism is crucial for most species. Here, we examined the ability of leptin, important in the control of energy metabolism, to induce leptin signaling at the molecular as well as the behavioral level throughout the 24-h day in mice fed either a control or a high-fat diet (HFD). Furthermore, we investigated the effects of time-restricted feeding (TRF; a limitation of HFD access to 6 h each day) on energy metabolism during different periods throughout the 24-h day. In control mice, molecular leptin sensitivity was highest at zeitgeber time (ZT)0 (lights on), declining during the light phase, and increasing during the dark phase. Surprisingly, leptin resistance in HFD-fed mice was only present from the middle of the dark to the middle of the light period. Specifically, when TRF occurred from ZT21 to ZT3 (when leptin resistance in HFD-fed mice was most profound), it resulted in a disruption of the daily rhythms of locomotor activity and energy expenditure and in increased plasma insulin levels compared with other TRF periods. These data provide evidence that leptin sensitivity is controlled by the circadian rhythm and that TRF periods may be most efficient when aligned with the leptin-sensitive period.-Boucsein, A., Rizwan, M. Z., Tups, A. Hypothalamic leptin sensitivity and health benefits of time-restricted feeding are dependent on the time of day in male mice.
Metabolic switching is impaired by aging and facilitated by ketosis independent of glycogen.
Hernandez Abbi,Truckenbrod Leah,Federico Quinten,Campos Keila,Moon Brianna,Ferekides Nedi,Hoppe Meagan,D'Agostino Dominic,Burke Sara
The ability to switch between glycolysis and ketosis promotes survival by enabling metabolism through fat oxidation during periods of fasting. Carbohydrate restriction or stress can also elicit metabolic switching. Keto-adapting from glycolysis is delayed in aged rats, but factors mediating this age-related impairment have not been identified. We measured metabolic switching between glycolysis and ketosis, as well as glycogen dynamics, in young and aged rats undergoing time-restricted feeding (TRF) with a standard diet or a low carbohydrate ketogenic diet (KD). TRF alone reversed markers of insulin-related metabolic deficits and accelerated metabolic switching in aged animals. A KD+TRF, however, provided additive benefits on these variables. Remarkably, the ability to keto-adapt was not related to glycogen levels and KD-fed rats showed an enhanced elevation in glucose following epinephrine administration. This study provides new insights into the mechanisms of keto-adaptation demonstrating the utility of dietary interventions to treat metabolic impairments across the lifespan.
Diet-related telomere shortening and chromosome stability.
Marcon Francesca,Siniscalchi Ester,Crebelli Riccardo,Saieva Calogero,Sera Francesco,Fortini Paola,Simonelli Valeria,Palli Domenico
Recent evidences have highlighted an influence of micronutrients in the maintenance of telomere length (TL). In order to explore whether diet-related telomere shortening had any physiological relevance and was accompanied by significant damage in the genome, in the present study, TL was assessed by terminal restriction fragment (TRF) analysis in peripheral blood lymphocytes of 56 healthy subjects for which detailed information on dietary habits was available and data were compared \with the incidence of nucleoplasmic bridges (NPBs), a marker of chromosomal instability related to telomere dysfunction visualised with the cytokinesis-blocked micronucleus assay. To increase the capability to detect even slight impairment of telomere function, the incidence of NPBs was also evaluated on cells exposed in vitro to ionising radiation. Care was taken to control for potential confounding factors that might influence TL, viz. age, hTERT genotype and smoking status. Data showed that higher consumption of vegetables was related with significantly higher mean TL (P = 0.013); in particular, the analysis of the association between micronutrients and mean TL highlighted a significant role of antioxidant intake, especially beta-carotene, on telomere maintenance (P = 0.004). However, the diet-related telomere shortening did not result in associated increased spontaneous or radiation-induced NPBs. The distribution of TRFs was also analysed and a slight prevalence of radiation-induced NPBs (P = 0.03) was observed in subjects with higher amount of very short TRFs (<2 kb). The relative incidence of very short TRFs was positively associate with ageing (P = 0.008) but unrelated to vegetables consumption and daily intake of micronutrients, suggesting that the degree of telomere erosion related with low dietary intake of antioxidants observed in this study was not so extensive to lead to chromosome instability.
Time-restricted feeding delays the emergence of the age-associated, neoplastic-prone tissue landscape.
Serra Monica,Marongiu Fabio,Pisu Maria Giuseppina,Serra Mariangela,Laconi Ezio
Aging increases the risk of cancer partly through alterations in the tissue microenvironment. Time-restricted feeding (TRF) is being proposed as an effective strategy to delay biological aging. In the present studies, we assessed the effect of long-term exposure to TRF on the emergence of the age-associated, neoplastic-prone tissue landscape. Animals were exposed to either feeding (ALF) or TRF for 18 months and then transplanted with hepatocytes isolated from pre-neoplastic nodules. Both groups were continued ALF and the growth of transplanted cells was evaluated 3 months later. A significant decrease in frequency of larger size clusters of pre-neoplastic hepatocytes was seen in TRF-exposed group compared to controls. Furthermore, TRF modified several parameters related to both liver and systemic aging towards the persistence of a younger phenotype, including a decrease in liver cell senescence, diminished fat accumulation and up-regulation of SIRT1 in the liver, down-regulation of plasma IGF-1, decreased levels of plasma lipoproteins and up-regulation of hippocampal brain-derived growth factor (BDNF).These results indicate that TRF was able to delay the onset of the neoplastic-prone tissue landscape typical of aging. To our knowledge, this is the first investigation to describe a direct beneficial effect of TRF on early phases of carcinogenesis.
Time-restricted feeding for prevention and treatment of cardiometabolic disorders.
Melkani Girish C,Panda Satchidananda
The Journal of physiology
The soaring prevalence of obesity and diabetes is associated with an increase in comorbidities, including elevated risk for cardiovascular diseases (CVDs). CVDs continue to be among the leading causes of death and disability in the United States. While increased nutritional intake from an energy-dense diet is known to disrupt metabolic homeostasis and contributes to the disease risk, circadian rhythm disruption is emerging as a new risk factor for CVD. Circadian rhythms coordinate cardiovascular health via temporal control of organismal metabolism and physiology. Thus, interventions that improve circadian rhythms are prospective entry points to mitigate cardiometabolic disease risk. Although light is a strong modulator of the neural circadian clock, time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs. We discovered that imposing a time-restricted feeding (TRF) regimen in which all caloric intakes occur consistently within ≤ 12 h every day exerts many cardiometabolic benefits. TRF prevents excessive body weight gain, improves sleep, and attenuates age- and diet-induced deterioration in cardiac performance. Using an integrative approach that combines Drosophila melanogaster (fruit fly) genetics with transcriptome analyses it was found that the beneficial effects of TRF are mediated by circadian clock, ATP-dependent TCP/TRiC/CCT chaperonin and mitochondrial electron transport chain components. Parallel studies in rodents have shown TRF reduces metabolic disease risks by maintaining metabolic homeostasis. As modern humans continue to live under extended periods of wakefulness and ingestion events, daily eating pattern offers a new potential target for lifestyle intervention to reduce CVD risk.
tRNA-Derived Small Non-Coding RNAs as Novel Epigenetic Molecules Regulating Adipogenesis.
Shen Linyuan,Tan Zhendong,Gan Mailin,Li Qiang,Chen Lei,Niu Lili,Jiang Dongmei,Zhao Ye,Wang Jinyong,Li Xuewei,Zhang Shunhua,Zhu Li
tRNA-derived fragments (tRFs), a novel type of non-coding RNA derived from tRNAs, play an important part in governing gene expressions at a post-transcriptional level. To date, the regulatory mechanism of tRFs governing fat deposition and adipogenesis is completely unknown. In this study, high fat diet was employed to induce an obese rat model, and tRFs transcriptome sequencing was conducted to identify differentially expressed tRFs that response to obesity. We found out that tRF, which promoted preadipocyte proliferation by increasing expressions of cell cycle regulatory factors, had the highest fold change in the 296 differentially expressed tRFs. Moreover, tRF also suppressed preadipocyte differentiation by reducing triglyceride content and lipid accumulation, and by decreasing expressions of genes that related to fatty acid synthesis. According to results of luciferase activity analysis, tRF directly targeted Kruppel-like factor (KLF) 9, KLF11, and KLF12, thus significantly suppressing mRNA expressions of these target genes. Moreover, tRF suppressed adipogenesis, accompanying by suppressing expressions of adipogenic transcription factors (, , and ). In conclusion, these results imply that tRF may act as a novel epigenetic molecule regulating adipogenesis and could provide a new strategy for the intervention treatment of obesity.
The potential of antioxidant-rich Maoberry (Antidesma bunius) extract on fat metabolism in liver tissues of rats fed a high-fat diet.
Ngamlerst Chattraya,Udomkasemsab Arunwan,Kongkachuichai Ratchanee,Kwanbunjan Karunee,Chupeerach Chaowanee,Prangthip Pattaneeya
BMC complementary and alternative medicine
BACKGOUND:Obesity and dyslipidemia are major risk factors associated with non-alcoholic fatty liver disease (NAFLD). NAFLD refers to the accumulation of fat in more than 5% of the liver without alcohol consumption. NAFLD is the most common liver disease and is rapidly becoming a global public health problem. Maoberry (Antidesma bunius) is a fruit rich in antioxidants, especially phenolic compounds, which are reported to have benefits for patients with NAFLD. METHODS:We evaluated the effect of Maoberry extract on fat metabolism in liver tissues of high fat diet-induced rats. Five (5) groups (n = 12) of male Sprague-Dawley (SD) rats were divided into those given a high fat diet with no treatment (HF), different dosages of Maoberry extracts (0.38 [ML], 0.76 [MM) and 1.52 [MH] g/kg body weight) and 10 mg/kg statin (STAT). The rats were fed a high fat diet for 4 weeks to induce obesity and subsequently continued more for 12 weeks with treatments of Maoberry extracts or STAT. The levels of triglyceride, liver enzymes, oxidative stress and inflammation markers, triglyceride synthesis regulators, and pathology of the liver in high fat diet-induced rats were investigated. RESULTS:Feeding Maoberry extract in MH groups resulted in decreasing levels of serum alanine aminotransferase (ALT), liver triglyceride, liver thiobarbituric acid reactive substances (TBARS) and mRNA expression of tumour necrosis factor (TNF)-α, interleukin (IL)-6, glycerol-3-phosphate acyltransferase (GPAT)-1 and acetyl-coenzyme A carboxylase (ACC) compared with the HF group (P < 0.05). Moreover, histopathological study of the liver showed reduced fat droplets in the Maoberry extract treatment groups, especially in MH groups and STAT treatment groups. CONCLUSIONS:The improvements of fat metabolism in liver tissues of rats fed a high-fat diet were observed in Maoberry extracts treatment groups. The underline mechanism that link to fat metabolism might be through the process accompanied with down-regulated the gene expression of key enzymes of lipid production, antioxidant activity, and anti-inflammation properties of Maoberry extracts which contains high levels of phenolic and flavonoid compounds.
Time-restricted feeding influences immune responses without compromising muscle performance in older men.
Gasmi Maha,Sellami Maha,Denham Joshua,Padulo Johnny,Kuvacic Goran,Selmi Walid,Khalifa Riadh
Nutrition (Burbank, Los Angeles County, Calif.)
OBJECTIVE:This study examined the effect of 12 wk of time-restricted feeding (TRF) on complete blood cell counts, natural killer cells, and muscle performance in 20- and 50-year-old men. METHODS:Forty active and healthy participants were randomly divided into young experimental, young control, aged experimental, and aged control group. Experimental groups participated in TRF. Before (P1) and after (P2) TRF, participants performed a maximal exercise test to quantify muscle power. Resting venous blood samples were collected for blood count calculation. RESULTS:No changes were identified in muscle power in all groups after TRF (P > 0.05). At P1, red cells, hemoglobin, and hematocrit were significantly higher in young participants compared with elderly participants (P < 0.05). At P2, this age effect was not found in red cells between the young experimental group and the aged experimental group (P > 0.05). At P1, white blood cells and neutrophils were significantly higher in young participants compared with elderly participants (P < 0.05). At P2, only neutrophils decreased significantly (P < 0.05) in experimental groups without significant (P > 0.05) difference among them. Lymphocytes decreased significantly in the aged experimental group at P2 (P < 0.05), whereas NKCD16 and NKCD56 decreased significantly in experimental groups at P2 (P < 0.05). TRF had no effect on CD3, CD4, and CD8 levels (P > 0.05). CONCLUSION:TRF decreases hematocrit, total white blood cells, lymphocytes, and neutrophils in young and older men. TRF may be effective in preventing inflammation by decreasing natural killer cells. As such, TRF could be a lifestyle strategy to reduce systemic low-grade inflammation and age-related chronic diseases linked to immunosenescence, without compromising physical performance.
Plasma Metabolomic Changes in Mice With Time-restricted Feeding-attenuated Spontaneous Metastasis of Lewis Lung Carcinoma.
Yan Lin,Rust Bret M,Picklo Matthew J
BACKGROUND/AIM:Time-restricted feeding (TRF) during the dark phase of the day restores metabolic homeostasis in mice. MATERIALS AND METHODS:We performed untargeted metabolomic analysis on plasma from mice subjected to TRF that attenuates high-fat diet-enhanced spontaneous metastasis of Lewis lung carcinoma (LLC). RESULTS:Twenty-four of 152 identified metabolites differed among the four dietary groups (non-LLC-bearing mice fed the AIN93G diet and LLC-bearing mice fed the AIN93G, the high-fat diet (HFD), or TRF of the HFD). Component 1 of sparse partial least squares-discriminant analysis showed a clear separation between non-LLC-bearing and LLC-bearing mice. Major metabolites responsible for the changes were elevations in α-tocopherol, docosahexaenoic acid, cholesterol, dihydrocholestrol, isoleucine, leucine, and phenylalanine and decreases in lactic acid and pyruvic acid in LLC-bearing mice particularly those fed the HFD. Time-restricted feeding shifted the metabolic profile of LLC-bearing mice towards that of non-LLC-bearing controls. CONCLUSION:Time-restricted feeding improves metabolic profile of LLC-bearing mice.
Safety and feasibility of various fasting-mimicking diets among people with multiple sclerosis.
Roman S N,Fitzgerald K C,Beier M,Mowry E M
Multiple sclerosis and related disorders
BACKGROUND:Fasting-mimicking diets have shown promise in experimental autoimmune encephalitis and are currently being investigated among people with multiple sclerosis (MS). Ensuring adherence to diet changes is critical to determining the efficacy of such interventions. OBJECTIVE:Our primary aim was to evaluate the safety and feasibility of several fasting-mimicking diets and investigate whether various levels of clinical support improve diet adherence among people with MS. Secondarily, this study evaluated the impact of fasting-mimicking diets on weight and patient-reported outcomes (PROs). METHODS:We conducted three pilot studies (two randomized controlled for 6 months; one randomized with transition to single arm) restricting either the amount or timing of calorie intake over 24 or 48 weeks. Interventions included calorie restriction (daily or intermittently) or time-restricted feeding. Adherence measures varied across studies but were collected at study visits along with weight and PRO data. RESULTS:A total of 90 participants enrolled; 70 completed the studies, with no serious adverse events reported. Overall adherence to the calorie restriction diets was poor. When participants were tasked with maintaining a diet in a pragmatic setting, neither previously completed intense clinical support and education, nor weekly electronic communication throughout the diet period appeared to improve diet adherence. Participants who were able to adhere to a calorie restriction diet predictably lost weight. In contrast to calorie restriction, adherence to a time-restricted feeding (TRF) diet was relatively good. No statistically significant changes in PROs were observed in an intention-to-treat analysis. CONCLUSION:The role diet may play in clinical outcomes in MS remains unknown, as class I evidence is lacking. Diet adherence remains a primary barrier to the feasible conduct of large, randomized controlled diet trials. Strict adherence to a TRF dietary change may be more feasible than calorie restriction and should be considered in future fasting-mimicking diet trials. ClinicalTrials.gov Registry:A Pilot Study of Intermittent Calorie Restriction in Multiple Sclerosis - NCT02647502. A Pragmatic Trial of Dietary Programs in People with Multiple Sclerosis (MS) - NCT02846558.
Effects of time-restricted feeding on body weight and metabolism. A systematic review and meta-analysis.
Pellegrini Marianna,Cioffi Iolanda,Evangelista Andrea,Ponzo Valentina,Goitre Ilaria,Ciccone Giovannino,Ghigo Ezio,Bo Simona
Reviews in endocrine & metabolic disorders
Restriction in meal timing has emerged as a promising dietary approach for the management of obesity and dysmetabolic diseases. The present systematic review and meta-analysis summarized the most recent evidence on the effect of time-restricted feeding (TRF) on weight-loss and cardiometabolic variables in comparison with unrestricted-time regimens. Studies involving TRF regimen were systematically searched up to January 2019. Effect size was expressed as weighted mean difference (WMD) and 95% confidence intervals (CI). A total of 11 studies, 5 randomized controlled trials and 6 observational, were included. All selected studies had a control group without time restriction; hours of fasting ranged from 12-h until 20-h and study duration from 4 to 8-weeks. Most studies involved the Ramadan fasting. TRF determined a greater weight-loss than control regimens (11 studies, n = 485 subjects) (WMD: -1.07 kg, 95%CI: -1.74 to -0.40; p = 0.002; I = 56.2%), unrelated to study design. The subgroup analysis showed an inverse association between TRF and fat free mass in observational studies (WMD: -1.33 kg, 95%CI: -2.55 to -0.11; p = 0.03; I = 0%). An overall significant reduction in fasting glucose concentrations was observed with TRF regimens (7 studies, n = 363 subjects) (WMD: -1.71 mg/dL, 95%CI: -3.20 to -0.21; p = 0.03; I = 0%), above all in trials (WMD:-2.45 mg/dL, 95%CI: -4.72 to -0.17; p = 0.03; I = 0%). No between-group differences in the other variables were found. TRF regimens achieved a superior effect in promoting weight-loss and reducing fasting glucose compared to approaches with unrestricted time in meal consumption. However, long-term and well-designed trials are needed to draw definitive conclusions.
Time-Restricted Feeding Improves Glucose Tolerance in Men at Risk for Type 2 Diabetes: A Randomized Crossover Trial.
Hutchison Amy T,Regmi Prashant,Manoogian Emily N C,Fleischer Jason G,Wittert Gary A,Panda Satchidananda,Heilbronn Leonie K
Obesity (Silver Spring, Md.)
OBJECTIVE:This study aimed to assess the effects of 9-hour time-restricted feeding (TRF), early (TRFe) or delayed (TRFd), on glucose tolerance in men at risk for type 2 diabetes. METHODS:Fifteen men (age 55 ± 3 years, BMI 33.9 ± 0.8 kg/m ) wore a continuous glucose monitor for 7 days of baseline assessment and during two 7-day TRF conditions. Participants were randomized to TRFe (8 am to 5 pm) or TRFd (12 pm to 9 pm), separated by a 2-week washout phase. Glucose, insulin, triglycerides, nonesterified fatty acids, and gastrointestinal hormone incremental areas under the curve were calculated following a standard meal on days 0 and 7 at 8 am (TRFe) or 12 pm (TRFd). RESULTS:TRF improved glucose tolerance as assessed by a reduction in glucose incremental area under the curve (P = 0.001) and fasting triglycerides (P = 0.003) on day 7 versus day 0. However, there were no mealtime by TRF interactions in any of the variables examined. There was also no effect of TRF on fasting and postprandial insulin, nonesterified fatty acids, or gastrointestinal hormones. Mean fasting glucose by continuous glucose monitor was lower in TRFe (P = 0.02) but not TRFd (P = 0.17) versus baseline, but there was no difference between TRF conditions. CONCLUSIONS:While only TRFe lowered mean fasting glucose, TRF improved glycemic responses to a test meal in men at risk for type 2 diabetes regardless of the clock time that TRF was initiated.
Time-restricted feeding alleviates cardiac dysfunction induced by simulated microgravity via restoring cardiac FGF21 signaling.
Wang Xin-Pei,Xing Chang-Yang,Zhang Jia-Xin,Zhou Jia-Heng,Li Yun-Chu,Yang Hong-Yan,Zhang Peng-Fei,Zhang Wei,Huang Yin,Long Jian-Gang,Gao Feng,Zhang Xing,Li Jia
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Dietary restriction has been well-described to improve health metrics, but whether it could benefit pathophysiological adaptation to extreme environment, for example, microgravity, remains unknown. Here, we investigated the effects of a daily rhythm of fasting and feeding without reducing caloric intake on cardiac function and metabolism against simulated microgravity. Male rats under ad libitum feeding or time-restricted feeding (TRF; food access limited to 8 hours every day) were subjected to hindlimb unloading (HU) to simulate microgravity. HU for 6 weeks led to left ventricular dyssynchrony and declined cardiac function. HU also lowered pyruvate dehydrogenase (PDH) activity and impaired glucose utilization in the heart. All these were largely preserved by TRF. TRF showed no effects on HU-induced loss of cardiac mass, but significantly improved contractile function of cardiomyocytes. Interestingly, TRF raised liver-derived fibroblast growth factor 21 (FGF21) level and enhanced cardiac FGF21 signaling as manifested by upregulation of FGF receptor-1 (FGFR1) expression and its downstream markers in HU rats. In isolated cardiomyocytes, FGF21 treatment improved PDH activity and glucose utilization, consequently enhancing cell contractile function. Finally, both liver-specific knockdown (KD) of FGF21 and cardiac-specific FGFR1 KD abrogated the cardioprotective effects of TRF in HU rats. These data demonstrate that TRF improves cardiac glucose utilization and ameliorates cardiac dysfunction induced by simulated microgravity, at least partially, through restoring cardiac FGF21 signaling, suggesting TRF as a potential countermeasure for cardioprotection in long-term spaceflight.
Time-restricted feeding during childhood has persistent effects on mice commensal microbiota.
Hu Dandan,Ye Yuqian,Mao Yilei,Liao Wenjun,Xu Wei
Annals of translational medicine
Background:Time-restricted feeding (TRF) has been proved to improve general health in adults. However, according to our previous study, this regimen failed to show similar protective effect in pediatric population. Gut microbiota has been proved to play a vital part in the whole process. Although previous studies have defined the commensal flora as a real-time indicator of health conditions in adults, our study aimed to investigate whether the unfavorable TRF feeding schedule during childhood would cause long-term variations in murine model. Methods:We randomly assigned 120 4-week-old Kunming mice (half male and half female) to four feeding regimens: TRF.AD, time-restricted feeding during the childhood phase before switched to ad libitum feeding pattern as adults; TRF.TRF, continuously treated with time-restricted feeding; AD.TRF, went through time-restricted feeding only in adulthood; AD.AD, always had ad libitum access to food. After 8 weeks of dietary intervention, faeces were harvested from 12-week-old adult mice (one subject per cage), and gut microbiota was subsequently analysed via DNA extraction and 16s rRNA sequencing. Results:Mice on identical diet for four weeks but went through different feeding patterns during childhood showed distinctive traits in gut microbiota. Differences existed in both the α diversity and specific groups of bacteria under different taxonomical levels. Conclusions:Feeding pattern in the childhood had long-term impact on mice gut flora that cannot be wiped out in adulthood.
Effects of intermittent fasting on glucose and lipid metabolism.
Antoni Rona,Johnston Kelly L,Collins Adam L,Robertson M Denise
The Proceedings of the Nutrition Society
Two intermittent fasting variants, intermittent energy restriction (IER) and time-restricted feeding (TRF), have received considerable interest as strategies for weight-management and/or improving metabolic health. With these strategies, the pattern of energy restriction and/or timing of food intake are altered so that individuals undergo frequently repeated periods of fasting. This review provides a commentary on the rodent and human literature, specifically focusing on the effects of IER and TRF on glucose and lipid metabolism. For IER, there is a growing evidence demonstrating its benefits on glucose and lipid homeostasis in the short-to-medium term; however, more long-term safety studies are required. Whilst the metabolic benefits of TRF appear quite profound in rodents, findings from the few human studies have been mixed. There is some suggestion that the metabolic changes elicited by these approaches can occur in the absence of energy restriction, and in the context of IER, may be distinct from those observed following similar weight-loss achieved via modest continuous energy restriction. Mechanistically, the frequently repeated prolonged fasting intervals may favour preferential reduction of ectopic fat, beneficially modulate aspects of adipose tissue physiology/morphology, and may also impinge on circadian clock regulation. However, mechanistic evidence is largely limited to findings from rodent studies, thus necessitating focused human studies, which also incorporate more dynamic assessments of glucose and lipid metabolism. Ultimately, much remains to be learned about intermittent fasting (in its various forms); however, the findings to date serve to highlight promising avenues for future research.
Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans.
Jamshed Humaira,Beyl Robbie A,Della Manna Deborah L,Yang Eddy S,Ravussin Eric,Peterson Courtney M
Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl ( = 0.0003) and glycemic excursions by 12 ± 3 mg/dl ( = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene and the autophagy gene (all < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; = 0.10) and also increased the expression of ( = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes ( < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.
Time-restricted feeding for the prevention of cardiometabolic diseases in high-stress occupations: a mechanistic review.
Waldman Hunter S,Renteria Liliana I,McAllister Matthew J
Factors such as shift work, poor diet, lack of physical activity, and irregular sleep patterns put men and women employed in high-stress occupations (e.g., firefighters, police officers) at risk for cardiometabolic diseases. Time-restricted feeding (TRF) is a new approach to combatting many of these diseases; it places an emphasis on when meals are consumed, rather than calorie content. By only manipulating the eating "window," and without changing the food composition of the diet, research in rodent models has shown promising results that have health implications in people, such as obesity prevention, improved insulin sensitivity, and decreased oxidative stress, inflammation, and cholesterol synthesis. Human trials remain limited and the current data are mixed with regard to TRF and improving health. Present findings suggest the timing of the feeding-fasting window, with feeding taking place in the waking hours and fasting in the evening hours, might offer the greatest benefit for improving cardiometabolic markers. Although additional human trials are needed, TRF might reset and synchronize metabolic "clocks" found throughout the body that are disturbed with obesity, shift work, and frequent eating. Therefore, TRF might offer an effective feeding-fasting paradigm with significant clinical implications for the management and treatment of cardiometabolic diseases observed in individuals in high-stress occupations in the United States and in the US population in general. This review outlines the current rodent and human evidence in these areas and the efficacy of TRF for improving human health.
The emerging roles of lipids in circadian control.
Adamovich Yaarit,Aviram Rona,Asher Gad
Biochimica et biophysica acta
Lipids play vital roles in a wide variety of cellular functions. They act as structural components in cell membranes, serve as a major form of energy storage, and function as key signaling molecules. Mounting evidence points towards a tight interplay between lipids and circadian clocks. In mammals, circadian clocks regulate the daily physiology and metabolism, and disruption of circadian rhythmicity is associated with altered lipid homeostasis and pathologies such as fatty liver and obesity. Concomitantly, emerging evidence suggest that lipids are embedded within the core clock circuitry and participate in circadian control. Recent advances in lipidomics methodologies and their application in chronobiology studies have shed new light on the cross talk between circadian clocks and lipid homeostasis. We review herein the latest literature related to the involvement of lipids in circadian clock's function and highlight the contribution of circadian lipidomics studies to our understanding of circadian rhythmicity and lipid homeostasis. This article is part of a Special Issue entitled Brain Lipids.
Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock.
Dyar Kenneth Allen,Hubert Michaël Jean,Mir Ashfaq Ali,Ciciliot Stefano,Lutter Dominik,Greulich Franziska,Quagliarini Fabiana,Kleinert Maximilian,Fischer Katrin,Eichmann Thomas Oliver,Wright Lauren Emily,Peña Paz Marcia Ivonne,Casarin Alberto,Pertegato Vanessa,Romanello Vanina,Albiero Mattia,Mazzucco Sara,Rizzuto Rosario,Salviati Leonardo,Biolo Gianni,Blaauw Bert,Schiaffino Stefano,Uhlenhaut N Henriette
Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.
An Ultradian Feeding Schedule in Rats Affects Metabolic Gene Expression in Liver, Brown Adipose Tissue and Skeletal Muscle with Only Mild Effects on Circadian Clocks.
de Goede Paul,Sen Satish,Su Yan,Foppen Ewout,Poirel Vincent-Joseph,Challet Etienne,Kalsbeek Andries
International journal of molecular sciences
Restricted feeding is well known to affect expression profiles of both clock and metabolic genes. However, it is unknown whether these changes in metabolic gene expression result from changes in the molecular clock or in feeding behavior. Here we eliminated the daily rhythm in feeding behavior by providing 6 meals evenly distributed over the light/dark-cycle. Animals on this 6-meals-a-day feeding schedule retained the normal day/night difference in physiological parameters including body temperature and locomotor activity. The daily rhythm in respiratory exchange ratio (RER), however, was significantly phase-shifted through increased utilization of carbohydrates during the light phase and increased lipid oxidation during the dark phase. This 6-meals-a-day feeding schedule did not have a major impact on the clock gene expression rhythms in the master clock, but did have mild effects on peripheral clocks. In contrast, genes involved in glucose and lipid metabolism showed differential expression. In conclusion, eliminating the daily rhythm in feeding behavior in rats does not affect the master clock and only mildly affects peripheral clocks, but disturbs metabolic rhythms in liver, skeletal muscle and brown adipose tissue in a tissue-dependent manner. Thereby, a clear daily rhythm in feeding behavior strongly regulates timing of peripheral metabolism, separately from circadian clocks.
Time-restricted feeding alters lipid and amino acid metabolite rhythmicity without perturbing clock gene expression.
Lundell Leonidas S,Parr Evelyn B,Devlin Brooke L,Ingerslev Lars R,Altıntaş Ali,Sato Shogo,Sassone-Corsi Paolo,Barrès Romain,Zierath Juleen R,Hawley John A
Time-restricted feeding (TRF) improves metabolism independent of dietary macronutrient composition or energy restriction. To elucidate mechanisms underpinning the effects of short-term TRF, we investigated skeletal muscle and serum metabolic and transcriptomic profiles from 11 men with overweight/obesity after TRF (8 h day) and extended feeding (EXF, 15 h day) in a randomised cross-over design (trial registration: ACTRN12617000165381). Here we show that muscle core clock gene expression was similar after both interventions. TRF increases the amplitude of oscillating muscle transcripts, but not muscle or serum metabolites. In muscle, TRF induces rhythmicity of several amino acid transporter genes and metabolites. In serum, lipids are the largest class of periodic metabolites, while the majority of phase-shifted metabolites are amino acid related. In conclusion, short-term TRF in overweight men affects the rhythmicity of serum and muscle metabolites and regulates the rhythmicity of genes controlling amino acid transport, without perturbing core clock gene expression.
Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.
Hatori Megumi,Vollmers Christopher,Zarrinpar Amir,DiTacchio Luciano,Bushong Eric A,Gill Shubhroz,Leblanc Mathias,Chaix Amandine,Joens Matthew,Fitzpatrick James A J,Ellisman Mark H,Panda Satchidananda
While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.
Tocotrienol-rich fraction supplementation reduces hyperglycemia-induced skeletal muscle damage through regulation of insulin signaling and oxidative stress in type 2 diabetic mice.
Lee Heaji,Lim Yunsook
The Journal of nutritional biochemistry
Chronic hyperglycemia induces impairment of muscle growth and development of diabetes mellitus (DM). Since skeletal muscle is the major site for disposal of ingested glucose, impaired glucose metabolism causes imbalance between protein synthesis and degradation which adversely affects physical mobility. In this study, we investigated the effect of tocotrienol-rich fraction (TRF) supplementation on skeletal muscle damage in diabetic mice. Diabetes was induced by a high-fat diet with streptozotocin (STZ) injection (100 mg/kg) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose levels≥250 mg/dl), normal control (CON) and diabetic control (DMC) groups were administrated with olive oil, while TRF treatment groups were administrated with TRF (dissolved in olive oil) at low dose (100 mg/kg BW, LT) or high dose (300 mg/kg BW, HT) by oral gavage for 12 weeks. TRF supplementation ameliorated muscle atrophy, plasma insulin concentration and homeostatic model assessment estimated insulin resistance in diabetic mice. Moreover, TRF treatment up-regulated IRS-1 and Akt levels accompanied by increased translocation of GLUT4. Furthermore, TRF increased mitochondrial biogenesis by activating SIRT1, SIRT3 and AMPK in diabetic skeletal muscle. These changes were in part mechanistically explained by reduced levels of skeletal muscle proteins related to oxidative stress (4-hydroxynonenal, protein carbonyls, Nrf2 and HO-1), inflammation (NFkB, MCP-1, IL-6 and TNF-α), and apoptosis (Bax, Bcl₂ and caspase-3) in diabetic mice. Taken together, these results suggest that TRF might be useful as a beneficial nutraceutical to prevent skeletal muscle atrophy associated with diabetes by regulating insulin signaling via AMPK/SIRT1/PGC1α pathways in type 2 diabetic mice.
Tocotrienols have a nephroprotective action against lipid-induced chronic renal dysfunction in rats.
Rashid Khan Mohammad,Ahsan Haseeb,Siddiqui Shabeena,Siddiqui Waseem A
Vitamin E is the generic term for a group of tocopherols and tocotrienols (T3). Hyperlipidemia has been known to cause progressive chronic renal dysfunction (CRD). Several investigators have reported that T3 have hypolipidemic and nephroprotective activity against free radical-related diseases. This study was conducted to determine if T3 as tocotrienol-rich fraction (TRF) from palm oil would protect against lipid-induced CRD in rats. For the induction of atherosclerosis and hyperlipidemia, Wistar male rats were fed an atherogenic diet containing 1.25% cholesterol, 0.5% cholic acid and 21% beef tallow (42.6% calories from fat). The atherogenic diet was given for 14 weeks to induce atherosclerosis. The control rats were given normal rat chow and drug control animals treated with TRF (100 mg/kg bw; orally). The first group was taken as disease control in which the animals were left untreated and given normal rat chow for six weeks, while the second group was treated with 100 mg TRF/kg bw. Atherosclerosis and renal functions were evaluated after six weeks of TRF treatment. Feeding an atherogenic diet to rats for 14 weeks resulted in dyslipidemia and impaired renal functions with decreased glomerular filtration rate. The treatment with TRF significantly reduced dyslipidemia and inhibited the development of CRD caused by atherogenic factors. These findings show that low-dose treatment of TRF may provide significant health benefits in the prevention of lipid-induced CRD. The study suggests that TRF is effective in preventing lipid-induced CRD.
Tocotrienols reverse cardiovascular, metabolic and liver changes in high carbohydrate, high fat diet-fed rats.
Wong Weng-Yew,Poudyal Hemant,Ward Leigh C,Brown Lindsay
Tocotrienols have been reported to improve lipid profiles, reduce atherosclerotic lesions, decrease blood glucose and glycated haemoglobin concentrations, normalise blood pressure in vivo and inhibit adipogenesis in vitro, yet their role in the metabolic syndrome has not been investigated. In this study, we investigated the effects of palm tocotrienol-rich fraction (TRF) on high carbohydrate, high fat diet-induced metabolic, cardiovascular and liver dysfunction in rats. Rats fed a high carbohydrate, high fat diet for 16 weeks developed abdominal obesity, hypertension, impaired glucose and insulin tolerance with increased ventricular stiffness, lower systolic function and reduced liver function. TRF treatment improved ventricular function, attenuated cardiac stiffness and hypertension, and improved glucose and insulin tolerance, with reduced left ventricular collagen deposition and inflammatory cell infiltration. TRF improved liver structure and function with reduced plasma liver enzymes, inflammatory cell infiltration, fat vacuoles and balloon hepatocytes. TRF reduced plasma free fatty acid and triglyceride concentrations but only omental fat deposition was decreased in the abdomen. These results suggest that tocotrienols protect the heart and liver, and improve plasma glucose and lipid profiles with minimal changes in abdominal obesity in this model of human metabolic syndrome.
The effects of royal jelly and tocotrienol-rich fraction on impaired glycemic control and inflammation through irisin in obese rats.
Irandoost Pardis,Mesri Alamdari Naimeh,Saidpour Atoosa,Shidfar Farzad,Roshanravan Neda,Asghari Jafarabadi Mohammad,Farsi Farnaz,Asghari Hanjani Nazanin,Vafa Mohammadreza
Journal of food biochemistry
The effects of royal jelly (RJ) and tocotrienol-rich fraction (TRF) on obesity-induced glucose intolerance and inflammation were assessed in the current study. Regarding irisin as an important adipomyokine that attenuates obesity-induced disorders, we evaluated whether RJ and TRF could exert their metabolism regulatory effects through irisin. Obese rats were fed a high-fat diet (HFD) with or without supplementation of RJ, TRF, or both, for 8 weeks. At the end of the intervention, weight, irisin, glycemic, and inflammatory indices were measured. The weight of the rats did not remarkably reduce in any of the groups. Glucose homeostasis and inflammation were improved when we added RJ and TRF to HFD. RJ elevated irisin concentration, but the effect of TRF on irisin was not noticeable. Our results indicated that, despite the lack of significant weight loss, RJ and TRF promoted healthy obesity. This improvement was mediated by irisin in RJ consuming rats. PRACTICAL APPLICATIONS: Obesity is a public health concern associated with several chronic disorders. The beneficial effects of irisin on obesity-related disorders are well-established. It is the first study assessing the effect of RJ and TRF as functional foods, with pharmacological and nutritional activities on obesity complications, through irisin mediation. Our study demonstrated that RJ exerts its metabolic regulatory effects by irisin as a mediator. Our investigation makes a remarkable contribution to the literature, because it suggests a new mechanism for the anti-obesity properties of RJ and TRF.
Time-restricted feeding plus resistance training in active females: a randomized trial.
Tinsley Grant M,Moore M Lane,Graybeal Austin J,Paoli Antonio,Kim Youngdeok,Gonzales Joaquin U,Harry John R,VanDusseldorp Trisha A,Kennedy Devin N,Cruz Megan R
The American journal of clinical nutrition
BACKGROUND:A very limited amount of research has examined intermittent fasting (IF) programs, such as time-restricted feeding (TRF), in active populations. OBJECTIVE:Our objective was to examine the effects of TRF, with or without β-hydroxy β-methylbutyrate (HMB) supplementation, during resistance training (RT). METHODS:This study employed a randomized, placebo-controlled, reduced factorial design and was double-blind with respect to supplementation in TRF groups. Resistance-trained females were randomly assigned to a control diet (CD), TRF, or TRF plus 3 g/d HMB (TRFHMB). TRF groups consumed all calories between 1200 h and 2000 h, whereas the CD group ate regularly from breakfast until the end of the day. All groups completed 8 wk of supervised RT and consumed supplemental whey protein. Body composition, muscular performance, dietary intake, physical activity, and physiological variables were assessed. Data were analyzed prior to unblinding using mixed models and both intention-to-treat (ITT) and per protocol (PP) frameworks. RESULTS:Forty participants were included in ITT, and 24 were included in PP. Energy and protein intake (1.6 g/kg/d) did not differ between groups despite different feeding durations (TRF and TRFHMB: ∼7.5 h/d; CD: ∼13 h/d). Comparable fat-free mass (FFM) accretion (+2% to 3% relative to baseline) and skeletal muscle hypertrophy occurred in all groups. Differential effects on fat mass (CD: +2%; TRF: -2% to -4%; TRFHMB: -4% to -7%) were statistically significant in the PP analysis, but not ITT. Muscular performance improved without differences between groups. No changes in physiological variables occurred in any group, and minimal side effects were reported. CONCLUSIONS:IF, in the form of TRF, did not attenuate RT adaptations in resistance-trained females. Similar FFM accretion, skeletal muscle hypertrophy, and muscular performance improvements can be achieved with dramatically different feeding programs that contain similar energy and protein content during RT. Supplemental HMB during fasting periods of TRF did not definitively improve outcomes. This study was prospectively registered at clinicaltrials.gov as NCT03404271.
Late-life time-restricted feeding and exercise differentially alter healthspan in obesity.
Schafer Marissa J,Mazula Daniel L,Brown Ashley K,White Thomas A,Atkinson Elizabeth,Pearsall Vesselina M,Aversa Zaira,Verzosa Grace C,Smith Leslie A,Matveyenko Aleksey,Miller Jordan D,LeBrasseur Nathan K
Aging and obesity increase multimorbidity and disability risk, and determining interventions for reversing healthspan decline is a critical public health priority. Exercise and time-restricted feeding (TRF) benefit multiple health parameters when initiated in early life, but their efficacy and safety when initiated at older ages are uncertain. Here, we tested the effects of exercise versus TRF in diet-induced obese, aged mice from 20 to 24 months of age. We characterized healthspan across key domains: body composition, physical, metabolic, and cardiovascular function, activity of daily living (ADL) behavior, and pathology. We demonstrate that both exercise and TRF improved aspects of body composition. Exercise uniquely benefited physical function, and TRF uniquely benefited metabolism, ADL behavior, and circulating indicators of liver pathology. No adverse outcomes were observed in exercised mice, but in contrast, lean mass and cardiovascular maladaptations were observed following TRF. Through a composite index of benefits and risks, we conclude the net healthspan benefits afforded by exercise are more favorable than those of TRF. Extrapolating to obese older adults, exercise is a safe and effective option for healthspan improvement, but additional comprehensive studies are warranted before recommending TRF.
Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity.
Chung Heekyung,Chou Winjet,Sears Dorothy D,Patterson Ruth E,Webster Nicholas J G,Ellies Lesley G
Metabolism: clinical and experimental
BACKGROUND:Menopause is associated with significant hormonal changes that result in increased total body fat and abdominal fat, amplifying the risk for metabolic syndrome and diseases such as diabetes, cardiovascular disease and cancer in postmenopausal women. Intermittent fasting regimens hold significant health benefit promise for obese humans, however, regimens that include extreme daytime calorie restriction or daytime fasting are generally associated with hunger and irritability, hampering long-term compliance and adoption in the clinical setting. Time-restricted feeding (TRF), a regimen allowing eating only during a specific period in the normal circadian feeding cycle, without calorie restriction, may increase compliance and provide a more clinically viable method for reducing the detrimental metabolic consequences associated with obesity. METHODS:We tested TRF as an intervention in a mouse model of postmenopausal obesity. Metabolic parameters were measured using Clinical Laboratory Animal Monitoring System (CLAMS) and we carried out glucose tolerance tests. We also stained liver sections with oil red O to examine steatosis and measured gene expression related to gluconeogenesis. RESULTS:Preexisting metabolic disease was significantly attenuated during 7 weeks of TRF. Despite having access to the same high fat diet (HFD) as ad libitum fed (ALF) mice, TRF mice experienced rapid weight loss followed by a delayed improvement in insulin resistance and a reduced severity of hepatic steatosis by having access to the HFD for only 8h during their normal nocturnal feeding period. The lower respiratory exchange ratio in the TRF group compared with the ALF group early in the dark phase suggested that fat was the predominant fuel source in the TRF group and correlated with gene expression analyses that suggested a switch from gluconeogenesis to ketogenesis. In addition, TRF mice were more physically active than ALF fed mice. CONCLUSIONS:Our data support further analysis of TRF as a clinically viable form of intermittent fasting to improve metabolic health due to obesity.
Effect of time-restricted feeding on metabolic risk and circadian rhythm associated with gut microbiome in healthy males.
Zeb Falak,Wu Xiaoyue,Chen Lijun,Fatima Sadia,Haq Ijaz-Ul,Chen Aochang,Majeed Fatima,Feng Qing,Li Min
The British journal of nutrition
Time-restricted feeding (TRF) confers protection against nutritional challenges that predispose obesity and metabolic risks through involvement of circadian locomotor output cycles protein kaput genes and gut microbiome, but the underlying mechanism is not clearly understood. Therefore, the present study examined the effects of TRF on metabolic markers and circadian rhythm associated with gut microbiota in healthy males. Two groups (TRF, n 56; non-TRF, n 24) of male adults were enrolled. The TRF group provided blood at pre-TRF and post-TRF, while non-TRF one time after 25 d of trial. Serum lipid and liver profiles were determined. Real time-PCR was applied for circadian and inflammatory gene expression. The 16S rRNA genes were sequenced on the Illumina Miseq v3 platform to comprehensively catalogue the composition and abundance of bacteria in stool. We showed that TRF ameliorated the serum lipid and liver profiles of the individuals. In the TRF group, gut microbial richness was significantly enhanced, with enrichment of Prevotellaceae and Bacteroideaceae. TRF enhanced circadian gene expression probably by activation of sirtuin-1, which is positively associated with gut microbiome richness. TRF could be a safe remedy for the prevention of metabolic diseases related to dyslipidaemia, as it regulates circadian rhythm associated with gut microbiome modulation.
Time-restricted feeding in young men performing resistance training: A randomized controlled trial.
Tinsley Grant M,Forsse Jeffrey S,Butler Natalie K,Paoli Antonio,Bane Annie A,La Bounty Paul M,Morgan Grant B,Grandjean Peter W
European journal of sport science
A randomized controlled trial was conducted to examine eight weeks of resistance training (RT) with and without time-restricted feeding (TRF) in order to assess nutrient intake and changes in body composition and muscular strength in young recreationally active males. The TRF programme consisted of consuming all calories within a four-hour period of time for four days per week, but included no limitations on quantities or types of foods consumed. The RT programme was performed three days per week and consisted of alternating upper and lower body workouts. For each exercise, four sets leading to muscular failure between 8 and 12 repetitions were employed. Research visits were conducted at baseline, four, and eight weeks after study commencement. Measurements of total body composition by dual-energy X-ray absorptiometry and muscle cross-sectional area by ultrasound were obtained. Upper and lower body strength and endurance were assessed, and four-day dietary records were collected. TRF reduced energy intake by ∼650 kcal per day of TRF, but did not affect total body composition within the duration of the study. Cross-sectional area of the biceps brachii and rectus femoris increased in both groups. Effect size data indicate a gain in lean soft tissue in the group that performed RT without TRF (+2.3 kg, d = 0.25). Upper and lower body strength and lower body muscular endurance increased in both groups, but effect sizes demonstrate greater improvements in the TRF group. Overall, TRF reduced energy intake and did not adversely affect lean mass retention or muscular improvements with short-term RT in young males.
Diet and feeding pattern affect the diurnal dynamics of the gut microbiome.
Zarrinpar Amir,Chaix Amandine,Yooseph Shibu,Panda Satchidananda
The gut microbiome and daily feeding/fasting cycle influence host metabolism and contribute to obesity and metabolic diseases. However, fundamental characteristics of this relationship between the feeding/fasting cycle and the gut microbiome are unknown. Our studies show that the gut microbiome is highly dynamic, exhibiting daily cyclical fluctuations in composition. Diet-induced obesity dampens the daily feeding/fasting rhythm and diminishes many of these cyclical fluctuations. Time-restricted feeding (TRF), in which feeding is consolidated to the nocturnal phase, partially restores these cyclical fluctuations. Furthermore, TRF, which protects against obesity and metabolic diseases, affects bacteria shown to influence host metabolism. Cyclical changes in the gut microbiome from feeding/fasting rhythms contribute to the diversity of gut microflora and likely represent a mechanism by which the gut microbiome affects host metabolism. Thus, feeding pattern and time of harvest, in addition to diet, are important parameters when assessing the microbiome's contribution to host metabolism.
Two-Week Isocaloric Time-Restricted Feeding Decreases Liver Inflammation without Significant Weight Loss in Obese Mice with Non-Alcoholic Fatty Liver Disease.
Wilson Rachel B,Zhang Richard,Chen Yun Jin,Peters Kia M,Sawyez Cynthia G,Sutherland Brian G,Patel Krisha,Kennelly John P,Leonard Kelly-Ann,Jacobs René L,Wang Rennian,Borradaile Nica M
International journal of molecular sciences
Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver and expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD.
Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males.
Moro Tatiana,Tinsley Grant,Bianco Antonino,Marcolin Giuseppe,Pacelli Quirico Francesco,Battaglia Giuseppe,Palma Antonio,Gentil Paulo,Neri Marco,Paoli Antonio
Journal of translational medicine
BACKGROUND:Intermittent fasting (IF) is an increasingly popular dietary approach used for weight loss and overall health. While there is an increasing body of evidence demonstrating beneficial effects of IF on blood lipids and other health outcomes in the overweight and obese, limited data are available about the effect of IF in athletes. Thus, the present study sought to investigate the effects of a modified IF protocol (i.e. time-restricted feeding) during resistance training in healthy resistance-trained males. METHODS:Thirty-four resistance-trained males were randomly assigned to time-restricted feeding (TRF) or normal diet group (ND). TRF subjects consumed 100 % of their energy needs in an 8-h period of time each day, with their caloric intake divided into three meals consumed at 1 p.m., 4 p.m., and 8 p.m. The remaining 16 h per 24-h period made up the fasting period. Subjects in the ND group consumed 100 % of their energy needs divided into three meals consumed at 8 a.m., 1 p.m., and 8 p.m. Groups were matched for kilocalories consumed and macronutrient distribution (TRF 2826 ± 412.3 kcal/day, carbohydrates 53.2 ± 1.4 %, fat 24.7 ± 3.1 %, protein 22.1 ± 2.6 %, ND 3007 ± 444.7 kcal/day, carbohydrates 54.7 ± 2.2 %, fat 23.9 ± 3.5 %, protein 21.4 ± 1.8). Subjects were tested before and after 8 weeks of the assigned diet and standardized resistance training program. Fat mass and fat-free mass were assessed by dual-energy x-ray absorptiometry and muscle area of the thigh and arm were measured using an anthropometric system. Total and free testosterone, insulin-like growth factor 1, blood glucose, insulin, adiponectin, leptin, triiodothyronine, thyroid stimulating hormone, interleukin-6, interleukin-1β, tumor necrosis factor α, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured. Bench press and leg press maximal strength, resting energy expenditure, and respiratory ratio were also tested. RESULTS:After 8 weeks, the 2 Way ANOVA (Time * Diet interaction) showed a decrease in fat mass in TRF compared to ND (p = 0.0448), while fat-free mass, muscle area of the arm and thigh, and maximal strength were maintained in both groups. Testosterone and insulin-like growth factor 1 decreased significantly in TRF, with no changes in ND (p = 0.0476; p = 0.0397). Adiponectin increased (p = 0.0000) in TRF while total leptin decreased (p = 0.0001), although not when adjusted for fat mass. Triiodothyronine decreased in TRF, but no significant changes were detected in thyroid-stimulating hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglycerides. Resting energy expenditure was unchanged, but a significant decrease in respiratory ratio was observed in the TRF group. CONCLUSIONS:Our results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males.
Time-restricted feeding attenuates gluconeogenic activity through inhibition of PGC-1α expression and activity.
She Yuqing,Sun Jingjing,Hou Pengfei,Fang Penghua,Zhang Zhenwen
Physiology & behavior
BACKGROUND:Time-restricted feeding (TRF), a key component of intermittent fasting regimens, has gained considerable attention in recent years due to reversing obesity and insulin resistance. To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of TRF against hepatic gluconeogenic activity in obese mice. METHODS:The obese mice were subjected to either ad lib or TRF of a high fat diet for 8 h per day for 4 weeks. Western blotting, qRT-PCR, and plasma biochemical analyses were applied. RESULTS:The present findings showed that TRF regimen reduced food intake, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in mice of high fat diet-induced obesity. Mechanistically, we confirmed that TRF regimen protected against hyperglycemia and ameliorated hepatic gluconeogenic activity through inhibition of p38 MAPK/SIRT1/PGC-1α signal pathway. CONCLUSION:Our findings suggest that TRF regimen might be a potential novel nonpharmacological strategy against obesity/diabetes-induced hyperglycemia and insulin resistance.
Effects of Royal Jelly and Tocotrienol Rich Fraction in obesity treatment of calorie-restricted obese rats: a focus on white fat browning properties and thermogenic capacity.
Mesri Alamdari Naimeh,Irandoost Pardis,Roshanravan Neda,Vafa Mohammadreza,Asghari Jafarabadi Mohammad,Alipour Shahriar,Roshangar Leila,Alivand Mohammadreza,Farsi Farnaz,Shidfar Farzad
Nutrition & metabolism
Background:Obesity has reached an alarming rate worldwide. Promoting thermogenesis via increasing the function of brown adipose tissue (BAT) or white adipose tissue (WAT) browning has been proposed as a new protective approach against obesity. The goal of this study was to evaluate the effects of Royal Jelly (RJ) and tocotrienol rich fraction (TRF) on BAT activation and WAT browning during calorie restriction diet (CRD) in obesity model. Methods:In this experimental study, 50 obese Wistar rats were randomly divided into 5 groups and then received one of the following treatments for a period of 8-week: High-fat diet (HFD), CRD, RJ + CRD, TRF + CRD, and RJ + TRF + CRD. Effects of RJ and TRF, individually and in combination on body weight and the expression of key thermoregulatory genes in WAT and BAT were examined by quantitative real-time (qRT-PCR). Also, morphological alterations were assessed by hematoxylin and eosin staining. Results:RJ (- 67.21 g ±4.84 g) and RJ + TRF (- 73.29 g ±4.51 g) significantly reduced weight gain relative to the CRD group (- 40.70 g ±6.50 g, < 0.001). In comparison with the CRD group, RJ and RJ + TRF remarkably enhanced the uncoupling protein1 expression in WAT (5.81, 4.72 fold, < 0.001) and BAT (4.99, 4.75 fold, < 0.001). The expression of PR domain containing 16, cAMP response element-binding protein1 , P38 mitogen-activated protein kinases and Bone morphogenetic protein8B have significantly increased following RJ and RJ + TRF treatments ( < 0.001). However the expression levels of CCAAT/enhancer-binding protein beta and Bone morphogenetic protein7 did not remarkably change. Multilocular beige cells in WAT and compacted dense adipocytes were also observed in BAT of RJ and RJ + TRF received groups. TRF showed no substantial effects on the expression of the mentioned thermoregulatory genes and brown fat-like phenotype. Conclusion:Our results suggest that, Royal Jelly promotes thermogenesis and browning of WAT, contributing to an increase in energy expenditure. Thus, Royal Jelly may give rise to a novel dietary choice to attenuate obesity.
Early or delayed time-restricted feeding prevents metabolic impact of obesity in mice.
Regmi Prashant,Chaudhary Rajesh,Page Amanda J,Hutchison Amy T,Vincent Andrew D,Liu Bo,Heilbronn Leonie
The Journal of endocrinology
Time-restricted feeding (TRF) initiated early during the dark phase prevents the metabolic consequences of a high-fat diet in rodent models. However, the metabolic consequences of delaying the initiation of TRF, akin to breakfast skipping in humans, is unclear. We assigned 8-week-old male C57BL/6J mice (n = 192) to chow or high-fat diet ad libitum (AL) for 4 weeks, before randomization to continue AL or 10 h of TRF, initiated at lights off (TRFe) or 4-h after lights off (TRFd) for a further 8 weeks. Oral glucose tolerance tests (1 g/kg), metabolic monitoring and body composition by echoMRI were performed, and tissues were collected at six time points. TRF reduced weight and fat mass vs AL, with a greater reduction in TRFe vs TRFd. TRF improved glucose tolerance and protected mice from high-fat diet-induced hepatosteatosis vs AL, with no difference between TRFe and TRFd. TRF increased the amplitude of Bmal1, Cry1, Per2, Nampt, and Nocturnin mRNA levels in liver. A phase delay in Bmal1, Cry1, Per2, Reverbα, Nampt, NAD, Sirt1, and Nocturnin was observed in TRFd. Thus, delaying TRF limited the weight benefit and induced a phase delay in the hepatic clock, but improved metabolic health. Allowing more flexibility in when TRF is initiated may increase the translational potential of this dietary approach in humans.
Identification of factors influencing motivation to undertake time-restricted feeding in humans.
Jefcoate Paul W,Robertson M Denise,Ogden Jane,Johnston Jonathan D
The interaction between time of day and energy intake, termed chrono-nutrition, has received considerable recent interest. One aspect of chrono-nutrition with potential to benefit long-term cardio-metabolic health is time-restricted feeding (TRF). Current support for TRF primarily derives from animal research, although recent small-scale human studies indicate possible translational benefit. Whether free-living humans, however, can incorporate TRF into their daily lives is poorly understood. This study reports data from participants (n = 608) who completed an online questionnaire to investigate daily routine, likelihood of TRF incorporation within work vs free-days, and key considerations influencing TRF uptake. The majority of participants reported a typical daily feeding window (time between first and last energy intake) of between 10 and 14 h on workdays and free days, 62.7 and 65.5% respectively. Likelihood of adherence to TRF declined with an increase in the proposed restriction of the feeding window by 0.5 to 4-h per day. We then examined data from participants with a typical daily feeding window of 12+ h on workdays (n = 221) and free-days (n = 223) to investigate the likelihood of using TRF, and the most important considerations in making this decision. Of these participants, (n = 132) on workdays and (n = 125) on free days would likely reduce their feeding window by 3-h. Multiple regression analysis revealed that key considerations determining the likelihood of adopting TRF were: cost, time availability, and perceived health benefits (on workdays); wake time, bed time, time availability, motivation to change and perceived health benefits (on free-days). These data provide novel information regarding public attitudes towards TRF and highlight important aspects to be considered when translating controlled laboratory studies to public dietary advice.
Determinants of Adherence in Time-Restricted Feeding in Older Adults: Lessons from a Pilot Study.
Lee Stephanie A,Sypniewski Caroline,Bensadon Benjamin A,McLaren Christian,Donahoo William T,Sibille Kimberly T,Anton Stephen
Time-restricted feeding (TRF) is a type of intermittent fasting in which no calories are commonly consumed for approximately 12-18 hours on a daily basis. The health benefits of this eating pattern have been shown in overweight adults, with improvements in cardiometabolic risk factors as well as the preservation of lean mass during weight loss. Although TRF has been well studied in younger and middle-aged adults, few studies have evaluated the effects of TRF in older adults. Thus, the goal of this study was to evaluate older-adult perspectives regarding the real-world advantages, disadvantages, and challenges to adopting a TRF eating pattern among participants aged 65 and over. A four-week single-arm pre- and post-test design was used for this clinical pilot trial TRF intervention study. Participants were instructed to fast for approximately 16 h per day with the daily target range between 14 and 18 h. Participants were provided with the TRF protocol at a baseline visit, along with a pictorial guide that depicted food items and beverages that were allowed and not allowed during fasting windows to reinforce that calorie-containing items were to be avoided. The trial interventionist called each participant weekly to promote adherence, review the protocol, monitor for adverse events, and provide support and guidance for any challenges faced during the intervention. Participants were instructed to complete daily eating time logs by recording the times at which they first consumed calories and when they stopped consuming calories. At the end of the intervention, participants completed an exit interview and a study-specific Diet Satisfaction Survey (Table 1) to assess their satisfaction, feasibility, and overall experience with the study intervention. Of the 10 participants who commenced the study (mean age = 77.1 y; 6 women, 4 men), nine completed the entire protocol. Seven of the ten participants reported easy adjustment to a 16-hour fast and rated the difference from normal eating patterns as minimal. Eight participants reported no decrease in energy during fasting periods, with greater self-reported activity levels in yardwork and light exercise. Adverse events were rare, and included transient headaches, which dissipated with increased water intake, and dizziness in one participant, which subsided with a small snack. The findings of the current trial suggest that TRF is an eating approach that is well tolerated by most older adults. Six participants, however, did not fully understand the requirements of the fasting regimen, despite being provided with specific instructions and a pictorial guide at a baseline visit. This suggests that more instruction and/or participant contact is needed in the early stages of a TRF intervention to promote adherence.
Therapeutic Time-restricted Feeding Reduces Renal Tumor Bioluminescence in Mice but Fails to Improve Anti-CTLA-4 Efficacy.
Turbitt William J,Orlandella Rachael M,Gibson Justin T,Peterson Courtney M,Norian Lyse A
BACKGROUND/AIM:Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS:Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS:TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION:Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.
Effects of alternate-day fasting on body weight and dyslipidaemia in patients with non-alcoholic fatty liver disease: a randomised controlled trial.
Cai Hua,Qin Yue-Lan,Shi Ze-Ya,Chen Jin-Hui,Zeng Min-Jie,Zhou Wei,Chen Ru-Qun,Chen Zhi-Yuan
BACKGROUND:Alternate-day fasting (ADF) is a novel diet therapy that may achieve reduction in body weight and improvement of dyslipidaemia, but the impact of this diet on patients with non-alcoholic fatty liver disease (NAFLD) remains unknown. The aim of this study was to evaluate the effects of ADF on the body weight and lipid profile of individuals with NAFLD. METHODS:NAFLD patients (n = 271) were randomised to the ADF group, time-restricted feeding (TRF) group, or the control group and subjected to the respective diet for 12 weeks. Anthropometric measurements (body weight, fat mass/fat-free mass) were performed, and plasma lipids were analysed enzymatically. RESULTS:Within 4 weeks, the body weight decreased significantly (P < 0.001) in the ADF group by 4.56 ± 0.41 kg (6.1 ± 0.5%) and the TRF group by 3.62 ± 0.65 kg (4.83 ± 0.9%) compared to the control group, and it decreased even more after 12 weeks in both groups (ADF: - 4.04 ± 0.54 kg, 5.4 ± 0.7%; TRF: - 3.25 ± 0.67 kg, 4.3 ± 0.9%). Fat mass was significantly reduced by ADF (- 3.49 ± 0.37 kg; 11 ± 1.2%) and TRF (- 2.91 ± 0.41 kg; 9.6 ± 1.3%), with ADF leading to a further reduction in fat mass after 12 weeks (- 3.48 ± 0.38 kg; 11 ± 1.2%). Total cholesterol was significantly decreased at both time points in the ADF group (- 0.91 ± 0.07 mmol/L; 18.5 ± 1.5%) compared to the control and TRF groups. Both ADF (- 0.64 ± 0.06 mmol/L; 25 ± 1.9%) and TRF (0.58 ± 0.07 mmol/L; 20 ± 1.7%) achieved a significant reduction in serum triglycerides (P < 0.001) after 12 weeks. Changes in fat free mass, HDL, LDL, fasting insulin, glucose, liver stiffness, and systolic or diastolic blood pressure did not differ between the groups. CONCLUSIONS:ADF appears to be an effective diet therapy for individuals with NAFLD that can achieve weight loss and improvement of dyslipidaemia within a relatively short period of time (4 to 12 weeks). Potential preventive effects of ADF on cardiovascular disease need to be confirmed by future investigations. TRIAL REGISTRATION:ChiCTR1900024411, this trial was retrospectively registered on July 10, 2019.
Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models.
Das Manasi,Ellies Lesley G,Kumar Deepak,Sauceda Consuelo,Oberg Alexis,Gross Emilie,Mandt Tyler,Newton Isabel G,Kaur Mehak,Sears Dorothy D,Webster Nicholas J G
Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.
Time-restricted feeding improves markers of cardiometabolic health in physically active college-age men: a 4-week randomized pre-post pilot study.
McAllister Matthew J,Pigg Brandon L,Renteria Liliana I,Waldman Hunter S
Nutrition research (New York, N.Y.)
Time-restricted feeding (TRF) has been shown to improve body composition, blood lipids, and reduce markers of inflammation and oxidative stress. However, most of these studies come from rodent models and small human samples, and it is not clear if the benefits are dependent upon a caloric deficit, or the time restriction nature of TRF. Based off of previous research, we hypothesized that humans following an ad libitum TRF protocol would reduce caloric intake and this caloric deficit would be associated with greater improvements in cardiometabolic health including blood pressure, body composition, blood lipids, and markers of inflammation and antioxidant status compared to an isocaloric TRF protocol. The purpose of this study was to: (1) examine the impact of TRF on markers of cardio-metabolic health and antioxidant status and (2) determine if the adaptations from TRF would differ under ad libitum compared to isocaloric conditions. Twenty-three healthy men were randomized to either an ad libitum or isocaloric 16:8 (fasting: feeding) TRF protocol. A total of 22 men completed the 28-day TRF protocol (mean ± SD; age: 22 ± 2.5 yrs.; height: 178.4 ± 6.9 cm; weight: 90.3 ± 24 kg; BMI: 28.5 ± 8.3 kg/m). Fasting blood samples were analyzed for glucose, lipids, as well as adiponectin, human growth hormone, insulin, cortisol, C-reactive protein, superoxide dismutase, total nitrate/nitrite, and glutathione. Time-restricted feeding in both groups was associated with significant (P < .05) reductions in body fat, blood pressure, and significant increases in adiponectin and HDL-c. No changes in caloric intake were detected. In summary, the results from this pilot study in metabolically healthy, active young men, suggest that TRF can improve markers of cardiometabolic health.
Metabolome of Mammary Tumors Differs from Normal Mammary Glands But Is Not Altered by Time-restricted Feeding Under Obesogenic Conditions.
Yan Lin,Sundaram Sneha,Rust Bret M,Picklo Matthew J,Bukowski Michael R
BACKGROUND/AIM:Time restricted feeding (TRF) mitigates the high-fat diet-enhanced mammary tumorigenesis in a MMTV-PyMT breast cancer model. MATERIALS AND METHODS:We performed untargeted metabolomic and targeted transcriptomic analyses on mammary tumors from MMTV-PyMT mice fed a standard AIN93G diet, a high-fat diet (HFD), or HFD with TRF (12 h, dark phase) and mammary glands from wild-type mice fed the AIN93G diet. RESULTS:The metabolic profile of mammary tumors differed from that of mammary glands; there was no impact of TRF upon tumor metabolome. TRF did reduce elevated expression of Hmgcr, Srebp1, Fads2, and Ppard in mammary tumors, indicating a down-regulation of lipid metabolism. CONCLUSION:The null effect of TRF on the metabolomic profile does not rule out changes in more refined intracellular signaling pathways. It suggests that the protection of TRF against mammary tumorigenesis may rely upon its action on the host rather than a direct effect on tumor metabolism.
The Ameliorative Effects of a Tocotrienol-Rich Fraction on the AGE-RAGE Axis and Hypertension in High-Fat-Diet-Fed Rats with Metabolic Syndrome.
Cheng Hong Sheng,Ton So Ha,Tan Joash Ban Lee,Abdul Kadir Khalid
The clinical value of tocotrienols is increasingly appreciated because of the unique therapeutic effects that are not shared by tocopherols. However, their effect on metabolic syndrome is not well-established. This study aimed to investigate the effects of a tocotrienol-rich fraction (TRF) from palm oil in high-fat-diet-treated rats. Male, post-weaning Sprague Dawley rats were provided high-fat (60% kcal) diet for eight weeks followed by a TRF (60 mg/kg) treatment for another four weeks. Physical, metabolic, and histological changes were compared to those on control and high-fat diets respectively. High-fat feeding for eight weeks induced all hallmarks of metabolic syndrome. The TRF reversed systolic and diastolic hypertension, hypercholesterolemia, hepatic steatosis, impaired antioxidant defense, and myeloperoxidase hyperactivity triggered by the high-fat diet. It also conferred an inhibitory effect on protein glycation to reduce glycated hemoglobin A1c and advanced glycation end products (AGE). This was accompanied by the suppression of the receptor for advanced glycation end product (RAGE) expression in the liver. The treatment effects on visceral adiposity, glycemic control, triglyceride level, as well as peroxisome proliferator-activated receptor α and γ expression were negligible. To conclude, treatment with a TRF exhibited protective effects on the cardiovascular and liver health in addition to the amelioration of plasma redox imbalance and AGE-RAGE activation. Further investigation as a therapy for metabolic syndrome is therefore worthwhile.
Nutraceutical properties of Leucaena leucocephala, Manihot esculenta, Cajanus cajan and a foliage blend in goat kids infected with Haemonchus contortus.
Minatchy Nathalie,Marie-Magdeleine Carine,Garin Miguel,Nimirf Ferdy,Romil-Granville Dimitri,Philibert Lucien,Calif Valeriuse,Bambou Jean-Christophe,Archimède Harry
Protein and condensed tannin-rich foliage (TRF) are potentially useful as nutraceuticals. The main objective of this study was to evaluate the diet and anthelmintic properties of three TRF types both individually and in combination. We hypothesized that synergistic or antagonistic effects on feed and anthelmintic values related to associations between TRF types may occur. Nutritional and anthelmintic characteristics of Leucaena leucocephala, Manihot esculenta, Cajanus cajan and a mixture of the compounds were evaluated using alfalfa pellets as a control. TRF ingredients were combined with Dichantium hay (48 and 52% of dry matter intake respectively) in mixed diets were consumed by Creole goat kids. Measurements were carried out in animals without parasites and in animals artificially infected with Haemonchus contortus. Individual feed intake and the digestibility of each diet was measured along with kid growth. There were no significant differences between the growth rates of pre-infected animals and animals fed mixed diets that included alfalfa. A strong anthelmintic activity is observed with Leucaena leucocephala contrary to other TRFs. This work confirms variable dietary and anthelmintic properties of TRF. The combination of TRF did not have synergistic or antagonistic effects on feed value or the anthelmintic potential of TRF.
A Delayed Morning and Earlier Evening Time-Restricted Feeding Protocol for Improving Glycemic Control and Dietary Adherence in Men with Overweight/Obesity: A Randomized Controlled Trial.
Parr Evelyn B,Devlin Brooke L,Radford Bridget E,Hawley John A
We determined the effects of time-restricted feeding (TRF; 8 h/d) versus extended feeding (EXF; 15 h/d) on 24-h and postprandial metabolism and subjective opinions of TRF in men with overweight/obesity. In a randomized crossover design, 11 sedentary males (age 38 ± 5 y; BMI: 32.2 ± 2.0 kg/m) completed two isoenergetic diet protocols for 5 days, consuming meals at 1000, 1300 and 1700 h (TRF) or 0700, 1400 and 2100 h (EXF). On Day 5, participants remained in the laboratory for 24 h, and blood samples were collected at hourly (0700-2300 h) then 2-hourly (2300-0700 h) intervals for concentrations of glucose, insulin and appetite/incretin hormones. Structured qualitative interviews were conducted following completion of both dietary conditions and investigated thematically. Total 24-h area under the curve (AUC) [glucose] tended to be lower for TRF versus EXF (-5.5 ± 9.0 mmol/L/h, = 0.09). Nocturnal glucose AUC was lower in TRF (-4.2 ± 5.8 mmol/L/h, = 0.04), with no difference in waking glucose AUC or AUC for [insulin]. Attitudes towards TRF were positive with improved feelings of well-being. Barriers to TRF were work schedules, family commitments and social events. Compared to extended feeding, short-term TRF improved nocturnal glycemic control and was positively perceived in men with overweight/obesity.
Time-restricted Feeding Attenuates High-fat Diet-enhanced Spontaneous Metastasis of Lewis Lung Carcinoma in Mice.
Yan Lin,Sundaram Sneha,Mehus Aaron A,Picklo Matthew J
BACKGROUND/AIM:Obesity is a risk factor for cancer. Disruption of the daily feeding and fasting rhythm can contribute to obesity. This study tested the hypothesis that time-restricted feeding (TRF) attenuates obesity-enhanced metastasis. MATERIALS AND METHODS:In a spontaneous metastasis model of Lewis lung carcinoma (LLC), male C57BL/6 mice were fed the standard AIN93G diet or a high-fat diet (HFD) with or without dark-phase restricted feeding (12 h per day) for 10 weeks. Pulmonary metastases from a subcutaneous tumor were quantified. RESULTS:The number and size of lung metastases were greater in the HFD group than in the AIN93G group, but did not differ between the TRF and AIN93G groups. TRF prevented HFD-induced increases in plasma concentrations of glucose, insulin, proinflammatory cytokines (leptin, monocyte chemotactic protein-1, plasminogen activator inhibitor-1), and angiogenic factors (angiopoietin-2, hepatic growth factor, vascular endothelial growth factor). CONCLUSION:TRF attenuates the HFD-enhanced spontaneous metastasis of LLC in mice.
Comparative hypoglycemic and nephroprotective effects of tocotrienol rich fraction (TRF) from palm oil and rice bran oil against hyperglycemia induced nephropathy in type 1 diabetic rats.
Siddiqui Shabeena,Rashid Khan Mohd,Siddiqui Waseem A
Diabetic nephropathy (DN) is a serious complication confronted by patients with diabetes. Available data indicate that the development of DN is linked to hyperglycemia. Tocotrienol rich fraction (TRF) from palm oil (PO) and rice bran oil (RBO) has been shown to lower the blood glucose level in patients and preclinical animal models. This study was designed to investigate if TRF from PO and RBO could improve the renal function in DN by the virtue of their hypoglycemic and antioxidant activities. Male Wistar rats having an average body weight (bw) 250g were divided into four groups of six each .The first group served as diabetic control [injected with 55mg/kg bw of streptozotocin (STZ), intraperitoneally], while the second and third group received PO-TRF and RBO-TRF, respectively, by gavage at a dose of 200mg/kg bw/day, over a period of 8 weeks post-induction of diabetes. The fourth group comprised of age-matched male Wistar rats that received single intraperitoneal injection of normal saline only and served as control. After 8 weeks of STZ injection and TRF treatment, 24h urine was collected and animals were sacrificed. Fasting blood glucose, glycosylated hemoglobin, biochemical markers of renal function and oxidative stress were evaluated in serum, urine and kidney tissue. The results show that treatment with PO-TRF as well as RBO-TRF significantly improved the glycemic status and renal function in type 1 diabetic rats but PO-TRF afforded greater efficiency at similar dose as compared to RBO-TRF. In conclusion, PO-TRF was found to be more effective hypoglycemic and nephroprotective agent in DN than RBO-TRF.
The effect of royal jelly and tocotrienol-rich fraction along with calorie restriction on hypothalamic endoplasmic reticulum stress and adipose tissue inflammation in diet-induced obese rats.
Irandoost Pardis,Mesri Alamdari Naimeh,Saidpour Atoosa,Shidfar Farzad,Farsi Farnaz,Asghari Jafarabadi Mohammad,Alivand Mohammad Reza,Vafa Mohammadreza
BMC research notes
OBJECTIVES:Endoplasmic reticulum (ER) stress causes adipose tissue dysfunction and chronic inflammation in obesity. Royal jelly (RJ) and tocotrienol-rich fraction (TRF) are reported to ameliorate inflammation. However, the improving effects of RJ and TRF on inflammation from ER stress modulating view have not been assessed so far. Hence, we investigated the effect of RJ and TRF on ER stress and some adipose tissue-derived inflammatory markers in the high-fat diet (HFD)-induced obesity. Wistar obese rats randomly allocated into 5 groups: HFD, calorie restriction diet (CRD), RJ + CRD, TRF + CRD, RJ + TRF + CRD. After 8-week intervention, adipose tissues and hypothalamus were dissected and serum was collected. RESULTS:RJ reduced glucose-regulated protein-78 (GRP78) expression as ER stress indicator in WAT and hypothalamus compared to CRD. Besides, RJ diminished the expression of inflammatory markers in white adipose tissue (WAT) and also decreased the serum concentration of them. TRF reduced inflammatory markers in the serum without remarkable effects on ER stress. Overall, RJ has protective effect against adipose tissue dysfunction and inflammation then suggested as a therapeutic approach to reduce some obesity-related complications. The impact of TRF in this regard is lower than RJ and limited to systemic inflammation improvement without remarkable changes in adipose tissue inflammation.
Time-restricted feeding on weekdays restricts weight gain: A study using rat models of high-fat diet-induced obesity.
Olsen Magnus Kringstad,Choi Man Hung,Kulseng Bård,Zhao Chun-Mei,Chen Duan
Physiology & behavior
A recent study reported that a special weekly scheduled time-restricted feeding regimen (TRF), i.e., no food consumption for 15h during the light (inactive) phase per day for 5 weekdays, attenuated the outcome of diverse nutritional challenges in response to high-fat diet in mice. In the present study, we wanted to further test whether this TRF could restrict body weight gain in both juvenile and adult animals when fed a high-fat diet. Fifty male Sprague-Dawley rats at ages from 5 to 27weeks were used. First, we found that freely fed rats with 60% fat diet gained weight significantly, which was associated with more calorie intake (particularly during light phase) than those fed standard food (7% fat). Secondly, we found that TRF restricted high-fat diet-induced weight gain in both groups of juvenile rats (5 and 13weeks of age) compared to freely fed rats with high-fat diet, despite the same levels of 24h-calorie intake during either weekdays or the weekend. Thirdly, we found that TRF did not restrict high-fat diet-induce weight gain in adult rats (27weeks of age). Thus, we suggest that this special TRF regimen could be further tested in humans (particularly young adults) for the purpose of obesity prevention.
Palm tocotrienol-rich fraction reduced plasma homocysteine and heart oxidative stress in rats fed with a high-methionine diet.
Norsidah Ku-Zaifah,Asmadi Ahmad Yusof,Azizi Ayob,Faizah Othman,Kamisah Yusof
Journal of physiology and biochemistry
Oxidative stress contributes to cardiovascular diseases. We aimed to study the effects of palm tocotrienol-rich fraction (TRF) on plasma homocysteine and cardiac oxidative stress in rats fed with a high-methionine diet. Forty-two male Wistar rats were divided into six groups. The first group was the control. Groups 2-6 were fed 1% methionine diet for 10 weeks. From week 6 onward, folate (8 mg/kg diet) or palm TRF (30, 60 and 150 mg/kg diet) was added into the diet of groups 3, 4, 5 and 6. The rats were then killed. Palm TRF at 150 mg/kg and folate supplementation prevented the increase in plasma total homocysteine (4.14 ± 0.33 and 4.30 ± 0.26 vs 5.49 ± 0.25 mmol/L, p < 0.05) induced by a high-methionine diet. The increased heart thiobarbituric acid reactive substance in rats fed with high-methionine diet was also prevented by the supplementations of palm TRF (60 and 150 mg/kg) and folate. The high-methionine group had a lower glutathione peroxidase activity (49 ± 3 vs 69 ± 4 pmol/mg protein/min) than the control group. This reduction was reversed by palm TRF at 60 and 150 mg/kg diet (p < 0.05), but not by folate. Catalase and superoxide dismutase activities were unaffected by both methionine and vitamin supplementations. In conclusion, palm TRF was comparable to folate in reducing high-methionine diet-induced hyperhomocysteinemia and oxidative stress in the rats' hearts. However, palm TRF was more effective than folate in preserving the heart glutathione peroxidase enzyme activity.
Time-restricted feeding reduces high-fat diet associated placental inflammation and limits adverse effects on fetal organ development.
Upadhyay Aditya,Anjum B,Godbole Nachiket M,Rajak Sangam,Shukla Pooja,Tiwari Swasti,Sinha Rohit A,Godbole Madan M
Biochemical and biophysical research communications
Maternal nutrition has become a major public health concern over recent years and is a known predictor of adverse long-term metabolic derangement in offspring. Time-restricted feeding (TRF), wherein food consumption is restricted to the metabolically active phase of the day, is a dietary approach that improves metabolic parameters when consuming a high-fat diet (HFD). Here, we tested whether TRF could reduce maternal HFD associated inflammation and thereby mitigate defects in fetal organ developmental. Female rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months prior to mating and continued throughout pregnancy. Rat dams were sacrificed at embryonic day 18.5 (ED18.5) and placental tissues from these rats were processed for the analysis of cellular apoptosis, inflammatory cytokines (TNFα and IL-6), oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Furthermore, fetal hepatic triglyceride (TG) content and fetal lung maturation were assessed at ED18.5. Biochemical analysis revealed that HFD-TRF rat had significantly lower serum TG levels and body weight compared to HFD-AL rats. Additionally, TRF significantly blocked HFD-induced placental apoptosis and inflammation via minimizing cellular stress, and restoring autophagic flux. In addition, fetal hepatosteatosis and delayed fetal lung maturation induced by HFD was significantly ameliorated in HFD-TRF compared to HFD-AL. Collectively, our results suggest that reducing placental inflammation via TRF could prevent adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.
Increased serotransferrin and ceruloplasmin turnover in diet-controlled patients with type 2 diabetes.
Golizeh Makan,Lee Kwangwon,Ilchenko Serguei,Ösme Abdullah,Bena James,Sadygov Rovshan G,Kashyap Sangeeta R,Kasumov Takhar
Free radical biology & medicine
Type 2 diabetes mellitus (T2DM) is associated with oxidative stress and perturbed iron metabolism. Serotransferrin (Trf) and ceruloplasmin (Cp) are two key proteins involved in iron metabolism and anti-oxidant defense. Non-enzymatic glycation and oxidative modification of plasma proteins are known to occur under hyperglycemia and oxidative stress. In this study, shotgun proteomics and HO-based metabolic labeling were used to characterize post-translational modifications and assess the kinetics of Trf and Cp in T2DM patients and matched controls in vivo. Six early lysine (Amadori) and one advanced arginine glycation were detected in Trf. No glycation, but five asparagine deamidations, were found in Cp. T2DM patients had increased fractional catabolic rates of both Trf and Cp that correlated with HbA (p < 0.05). The glycated Trf population was subject to an even faster degradation compared to the total Trf pool, suggesting that hyperglycemia contributed to an increased Trf degradation in T2DM patients. Enhanced production of Trf and Cp kept their levels stable. The changes in Trf and Cp turnover were associated with increased systemic oxidative stress without any alteration in iron status in T2DM. These findings can help better understand the potential role of altered Trf and Cp metabolism in the pathogenesis of T2DM and other diseases.
Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice.
Kentish Stephen J,Hatzinikolas George,Li Hui,Frisby Claudine L,Wittert Gary A,Page Amanda J
The Journal of neuroscience : the official journal of the Society for Neuroscience
Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice ( = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either or only during the light phase [Zeitgeber time (ZT) 0-12] or dark phase (ZT12-24) for 8 weeks. A subgroup of mice from all conditions ( = 8/condition) were placed in metabolic cages. After 12 weeks, GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were dampened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food-related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity. Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.
Time-restricted feeding ameliorates maternal high-fat diet-induced fetal lung injury.
Upadhyay Aditya,Sinha Rohit A,Kumar Alok,Godbole Madan M
Experimental and molecular pathology
Maternal inflammation ensuing from high-fat diet (HFD) intake during pregnancy is related to spontaneous preterm birth and respiratory impairment among premature infants. Recently, a circadian aligned dietary intervention referred to as Time-restricted feeding (TRF) has been reported to have beneficial metabolic effects. This study aimed to assess the effects of maternal TRF on fetal lung injury caused by maternal HFD intake. Female Wistar rats were kept on following three dietary regimens; Ad libitum normal chow diet (NCD-AL), Ad libitum HFD (HFD-AL) and Time-restricted fed HFD (HFD-TRF) from 5 months before mating and continued through pregnancy. Fetal lung samples were collected on the embryonic day 18.5, and apoptotic and inflammatory markers were assessed using TUNEL assay, western blotting, and qRT-PCR. Our results showed that TRF considerably prevented maternal HFD-induced apoptosis in fetal lung tissue that corroborated with a reduction in caspase activation and increased levels of anti-apoptotic BCL2 family proteins together with a lower level of ER-stress and autophagy markers including ATF6, CHOP and LC3-II. Besides, fetal lungs from HFD-TRF dams exhibited reduced expression of inflammatory genes that correlated with reduction and apoptotic injury throughout fetal development. Our results thus put forth TRF as a unique non-pharmacological approach to boost perinatal health beneath metabolic stress.
Time-restricted feeding of a high-fat diet in male C57BL/6 mice reduces adiposity but does not protect against increased systemic inflammation.
Delahaye Laura B,Bloomer Richard J,Butawan Matthew B,Wyman Jacqueline M,Hill Jessica L,Lee Harold W,Liu Andrew C,McAllan Liam,Han Joan C,van der Merwe Mariè
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
Time-restricted feeding (TRF) limits the duration of food availability without altering diet composition and can combat obesity in humans and mice. For this study we evaluated the effect of timing of food access during a TRF protocol on weight gain, adiposity, and inflammation. Young male C57BL/6 mice were placed on a high-fat (HF) diet (45% fat) for 8 weeks. Food access was unrestricted (HF) or restricted to 6 h per day, either for the first half (HF-early) or the second half (HF-late) of the active phase to resemble a window of time for food consumption early or late in the day in a human population. Weight, obesity-associated parameters, and inflammation were measured. TRF reduced weight gain over the 8-week period in mice consuming the same high-fat diet. Consistent with decreased weight gain in the TRF groups, body fat percentage, liver triglycerides, and plasma leptin and cholesterol levels were reduced. Adipose tissue inflammation, measured by CD11bF4/80 macrophage infiltration, was reduced in both TRF groups, but systemic tumor necrosis factor-α was increased in all groups consuming the high-fat diet. The HF-late group gained more weight than the HF-early group and had increased insulin resistance, while the HF-early group was protected. Therefore, a TRF protocol is beneficial for weight management when a high-fat diet is consumed, with food consumption earlier in the day showing greater health benefits. However, increased inflammatory markers in the TRF groups suggest that diet components can still increase inflammation even in the absence of overt obesity.
Time-restricted feeding reduces adiposity in mice fed a high-fat diet.
Sundaram Sneha,Yan Lin
Nutrition research (New York, N.Y.)
Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet-induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8hours during the dark cycle was initiated when high-fat diet-fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet-induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance.
Time-restricted feeding mice a high-fat diet induces a unique lipidomic profile.
Mehus Aaron A,Rust Bret,Idso Joseph P,Hanson Benjamin,Zeng Huawei,Yan Lin,Bukowski Michael R,Picklo Matthew J
The Journal of nutritional biochemistry
Time-restricted feeding (TRF) can reduce adiposity and lessen the co-morbidities of obesity. Mice consuming obesogenic high-fat (HF) diets develop insulin resistance and hepatic steatosis, but have elevated indices of long-chain polyunsaturated fatty acids (LCPUFA) that may be beneficial. While TRF impacts lipid metabolism, scant data exist regarding the impact of TRF upon lipidomic composition of tissues. We (1) tested the hypothesis that TRF of a HF diet elevates LCPUFA indices while preventing insulin resistance and hepatic steatosis and (2) determined the impact of TRF upon the lipidome in plasma, liver, and adipose tissue. For 12 weeks, male, adult mice were fed a control diet ad libitum, a HF diet ad libitum (HF-AL), or a HF diet with TRF, 12 hours during the dark phase (HF-TRF). HF-TRF prevented insulin resistance and hepatic steatosis resulting from by HF-AL treatment. TRF-blocked plasma increases in LCPUFA induced by HF-AL treatment but elevated concentrations of triacylglycerols and non-esterified saturated fatty acids. Analysis of the hepatic lipidome demonstrated that TRF did not elevate LCPUFA while reducing steatosis. However, TRF created (1) a separate hepatic lipid signature for triacylglycerols, phosphatidylcholine, and phosphatidylethanolamine species and (2) modified gene and protein expression consistent with reduced fatty acid synthesis and restoration of diurnal gene signaling. TRF increased the saturated fatty acid content in visceral adipose tissue. In summary, TRF of a HF diet alters the lipidomic profile of plasma, liver, and adipose tissue, creating a third distinct lipid metabolic state indicative of positive metabolic adaptations following HF intake.
Restricted feeding for 9h in the active period partially abrogates the detrimental metabolic effects of a Western diet with liquid sugar consumption in mice.
Woodie Lauren N,Luo Yuwen,Wayne Michael J,Graff Emily C,Ahmed Bulbul,O'Neill Ann Marie,Greene Michael W
Metabolism: clinical and experimental
BACKGROUND:Obesity is a major public health concern that can result from diets high in fat and sugar, including sugar sweetened beverages. A proposed treatment for dietary-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. Although TRF shows great promise to prevent obesity and the development of chronic disease, the effects of TRF to reverse metabolic changes and the development of NAFLD in animal models of a Western diet with sugary water consumption is not known. OBJECTIVE:The objective of the current study was to evaluate the role of TRF in the treatment of obesity and NAFLD through examination of changes in metabolic and histopathologic parameters. METHODS:To better understand the role of TRF in the treatment of obesity and NAFLD, we investigated the metabolic phenotype and NAFLD parameters in a mouse model of NAFLD in which obesity and liver steatosis are induced by a Western Diet (WD): a high-fat diet of lard, milkfat and Crisco with sugary drinking water. Mice were subjected to a short-term (4-weeks) and long-term (10-weeks) TRF in which food was restricted to 9h at night. RESULTS:Prior to TRF treatment, the WD mice had increased body mass, and exhibited less activity, and higher average daytime energy expenditure (EE) than chow fed mice. Approximately 4- and 10-weeks following TFR treatment, WD-TRF had moderate but not statistically significant weight loss compared to WD-ad libitum (WD-AL) mice. There was a modest but significant reduction in the inguinal adipose tissue weight in both WD-TRF groups compared to the WD-AL groups; however, there was no difference in epididymal and retroperitoneal adipose tissue mass or adipocyte size distribution. In contrast, the diet-induced increase in normalized liver tissue weight, hepatic triglyceride, and NAFLD score was partially abrogated in the 4-week WD-TRF mice, while systemic insulin resistance was partially abrogated and glucose intolerance was completely abrogated in the 10-week WD-TRF mice. Importantly, WD-induced metabolic dysfunction (substrate utilization, energy expenditure, and activity) was partially abrogated by 4- and 10-week TRF. CONCLUSIONS:Our results support the hypothesis that TRF aids in reducing the detrimental metabolic effects of consuming a WD with sugary drinking water but does not ameliorate obesity.
Time-Restricted Feeding Improves Body Weight Gain, Lipid Profiles, and Atherogenic Indices in Cafeteria-Diet-Fed Rats: Role of Browning of Inguinal White Adipose Tissue.
Aouichat Samira,Chayah Meriem,Bouguerra-Aouichat Souhila,Agil Ahmad
Time-restricted feeding (TRF) showed a potent effect in preventing obesity and improving metabolicoutcomes in several animal models of obesity. However, there is, as of yet, scarce evidence concerning its effectiveness against obesogenic challenges that more accurately mimic human Western diets, such as the cafeteria diet. Moreover, the mechanism for its efficacy is poorly understood. White adipose browning has been linked to body weight loss. Herein, we tested whether TRF has the potential to induce browning of inguinal white adipose tissue (iWAT) and to attenuate obesity and associated dyslipidemia in a cafeteria-diet-induced obesity model. Male Wistar rats were fed normal laboratory chow (NC) or cafeteria diet (CAF) for 16 weeks and were subdivided into two groups that were subjected to either ad libitum (ad lib, A) or TRF (R) for 8 h per day. Rats under the TRF regimen had a lower body weight gain and adiposity than the diet-matchedad lib rats, despite equivalent levels of food intake and locomotor activity. In addition, TRF improved the deranged lipid profile (total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c)) and atherogenic indices (atherogenic index of plasma (AIP), atherogenic coefficient (AC), coronary risk index (CRI) in CAF-fed rats. Remarkably, TRF resulted in decreased size of adipocytes and induced emergence of multilocular brown-like adipocytes in iWAT of NC- and CAF-fed rats. Protein expression of browning markers, such as uncoupling protein-1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), were also up-regulated in the iWAToftime-restricted NC- or CAF-fed rats. These findings suggest that a TRF regimen is an effective strategy to improve CAF diet-induced obesity, probably via a mechanismthe involving WAT browning process.
Time-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat diet.
Vieira Renan Fudoli Lins,Muñoz Vitor Rosetto,Junqueira Rafael Lima,de Oliveira Fellipe,Gaspar Rafael Calais,Nakandakari Susana Castelo Branco Ramos,Costa Suleyma de Oliveira,Torsoni Marcio Alberto,da Silva Adelino S R,Cintra Dennys Esper,de Moura Leandro Pereira,Ropelle Eduardo Rochete,Zaghloul Iman,Mekary Rania A,Pauli José Rodrigo
The Journal of physiology
KEY POINTS:Time-restricted feeding (TRF, in which energy intake is restricted to 8 h/day during the dark phase) alone or combined with aerobic exercise (AE) training can prevent weight gain and metabolic disorders in Swiss mice fed a high-fat diet. The benefits of TRF combined with AE are associated with improved hepatic metabolism and decreased hepatic lipid accumulation. TRF combined with AE training increased fatty acid oxidation and decreased expression of lipogenic and gluconeogenic genes in the liver of young male Swiss mice. TRF combined with AE training attenuated the detrimental effects of high-fat diet feeding on the insulin signalling pathway in the liver. ABSTRACT:Time-restricted feeding (TRF) or physical exercise have been shown to be efficient in the prevention and treatment of metabolic disorders; however, the additive effects of TRF combined with aerobic exercise (AE) training on liver metabolism have not been widely explored. In this study TRF (8 h in the active phase) and TRF combined with AE (TRF+Exe) were compared in male Swiss mice fed a high-fat diet, with evaluation of the effects on insulin sensitivity and expression of hepatic genes involved in fatty acid oxidation, lipogenesis and gluconeogenesis. As in previous reports, we show that TRF alone (eating only between zeitgeber time 16 and 0) was sufficient to reduce weight and adiposity gain, increase fatty acid oxidation and decrease lipogenesis genes in the liver. In addition, we show that mice of the TRF+Exe group showed additional adaptations such as increased oxygen consumption ( ), carbon dioxide production ( ) and production of ketone bodies (β-hydroxybutyrate). Also, TRF+Exe attenuated the negative effects of high-fat diet feeding on the insulin signalling pathway (insulin receptor, insulin receptor substrate, Akt), and led to increased fatty acid oxidation (Ppara, Cpt1a) and decreased gluconeogenic (Fbp1, Pck1, Pgc1a) and lipogenic (Srebp1c, Cd36) gene expression in the liver. These molecular results were accompanied by increased glucose metabolism, lower serum triglycerides and reduced hepatic lipid content in the TRF+Exe group. The data presented in this study show that TRF alone has benefits but TRF+Exe has additive benefits and can mitigate the harmful effects of consuming a high-fat diet on body adiposity, liver metabolism and glycaemic homeostasis in young male Swiss mice.