Maternal obesity increases the risk and severity of NAFLD in offspring.
Hagström Hannes,Simon Tracey G,Roelstraete Bjorn,Stephansson Olof,Söderling Jonas,Ludvigsson Jonas F
Journal of hepatology
BACKGROUND & AIMS:Maternal obesity has been linked to the development of cardiovascular disease and diabetes in offspring, but its relationship to non-alcoholic fatty liver disease (NAFLD) is unclear. METHODS:Through the nationwide ESPRESSO cohort study we identified all individuals ≤25 years of age in Sweden with biopsy-verified NAFLD diagnosed between 1992 and 2016 (n = 165). These were matched by age, sex, and calendar year with up to 5 controls (n = 717). Through linkage with the nationwide Swedish Medical Birth Register (MBR) we retrieved data on maternal early-pregnancy BMI, and possible confounders, in order to calculate adjusted odds ratios (aORs) for NAFLD in offspring. RESULTS:Maternal BMI was associated with NAFLD in offspring: underweight (aOR 0.84; 95% CI 0.14-5.15), normal weight (reference, aOR 1), overweight (aOR 1.51; 0.95-2.40), and obese (aOR 3.26; 1.72-6.19) women. Severe NAFLD (biopsy-proven fibrosis or cirrhosis) was also more common in offspring of overweight (aOR 1.94; 95% CI 0.96-3.90) and obese (aOR 3.67; 95% CI 1.61-8.38) mothers. Associations were similar after adjusting for maternal pre-eclampsia and gestational diabetes. Socio-economic parameters (smoking, mother born outside the Nordic countries and less than 10 years of basic education) were also associated with NAFLD in offspring but did not materially alter the effect size of maternal BMI in a multivariable model. CONCLUSIONS:This nationwide study found a strong association between maternal overweight/obesity and future NAFLD in offspring. Adjusting for socio-economic and metabolic parameters in the mother did not affect this finding, suggesting that maternal obesity is an independent risk factor for NAFLD in offspring. LAY SUMMARY:In a study of all young persons in Sweden with a liver biopsy consistent with fatty liver, the authors found that compared to matched controls, the risk of fatty liver was much higher in those with obese mothers. This was independent of available confounders and suggests that the high prevalence of obesity in younger persons might lead to a higher risk of fatty liver in their offspring.
Dynapenic abdominal obesity in hospitalized elderly patients with acute myocardial infarction.
da Silva Clécia Alves,Mendes Roberta Maria Lins,de Moraes Santana Natália,Dos Santos Natalia Fernandes,Pinho Cláudia Porto Sabino
Obesity and dynapenia are cardiovascular risk factors. When present together, it is called dynapenic abdominal obesity and can potentiate adverse outcomes. This study aims to estimate the prevalence of dynapenic abdominal obesity and its relationship with prognostic markers in patients with acute myocardial infarction (AMI). This is a hybrid study with a longitudinal component plus a cross-sectional component at baseline involving elderly patients admitted to a reference hospital in cardiology due to AMI in the Brazilian Northeast from May to October 2015. We analyzed patients' admission data and evaluated some prognostic markers up to two years after admission. We established abdominal obesity by measuring waist circumference (>102 cm for men and >88 cm for women) and dynapenia by handgrip strength (<27 kg/F for men and <16 kg/F for women). We considered the prognostic markers troponin and creatinine kinase - MB (CKMB), AMI classification according to ST segment elevation, TIMI score, need for coronary angioplasty or coronary artery bypass surgery, complications during hospitalization and within two years after admission, and re-admission to the same service. We evaluated 92 patients with a mean age of 71.4 ± 7.5 years. The prevalence of abdominal obesity and dynapenia was 56.5% and 44.6%, respectively. The coexistence of the two conditions occurred in 25.0% of the patients, being higher among women (p < 0.001). When comparing the dynapenic abdominal obese groups with the group of patients who had one of the two isolated conditions we observed that, for a same mean age and clinical characteristics, patients with only one of the conditions had a higher CKMB (p = 0.046) and troponin median (p = 0.032). The presence of dynapenia in the groups of abdominal obese and non-abdominal obese individuals is not associated with risk marker parameters (p > 0.05). High prevalence of abdominal obesity and dynapenia occurred among patients with AMI and in a quarter of these both conditions coexisted. Dynapenic abdominal obesitydoes not increase the risk of adverse outcomes and isolated dynapenia is not a marker of a poor prognosis.
Subtyping youngsters with obesity: A theory-based cluster analysis.
Vervoort L,Naets T,Goossens L,Verbeken S,Claes L,Tanghe A,Braet C
Psychological mechanisms play a crucial role in explaining weight gain. Aim of the present study was to identify subtypes in youngsters with obesity in line with these mechanisms. Defining homogeneous clusters within this heterogeneous group provides relevant information for personalized treatments. Data were collected in N = 572 participants (51% boys, aged 7-19) with extreme obesity (%BMI M = 187.8; SD = 30.9) recruited in an inpatient treatment centre. Based on psychological models of overweight/obesity, the Affect Regulation Model, the Reward Deficiency Model and The Dual Pathway Model, cluster variables were selected assessing emotional eating, reward reactivity and regulative capacities. Youngsters reported on emotional eating (DEBQ Emotional Eating) and reward sensitivity (BAS), while parents reported on children's regulative Executive Functions (BRIEF). Characteristics of the different clusters were examined concerning weight variables (pre and post treatment) and variables indexing problematic eating (DEBQ External Eating, Ch-EDE), affect regulation (FEEL-KJ) and depressive symptoms (CDI). Hierarchical cluster analyses supported the presence of three clusters, further evaluated by K-means cluster analyses. The cluster solutions differed according to age and sex (boys 7-13, boys 14-19, girls 7-13, girls 14-19). In all four age and gender subsamples, an "Emotional Eating" cluster displaying a vulnerable profile (high depression, maladaptive emotion regulation, problematic eating) and a "Reward Deficiency" cluster displaying a more resilient profile were detected. In girls 7-13, a "Weak Executive Functioning" indicative of insufficient self-regulative capacities, showed moderate to high emotional problems and problematic eating. In the other subgroups, the "Mean Level Functioning" cluster also showed elevated emotional problems and problematic eating. Given that different clusters can be identified, and given that these clusters have different profiles on emotional problems and problematic eating, subtyping youngsters with severe obesity is indicated, setting the stage for personalized treatments.
Metabolically healthy obesity and cardiovascular events: A nationwide cohort study.
Fauchier Grégoire,Bisson Arnaud,Bodin Alexandre,Herbert Julien,Semaan Carl,Angoulvant Denis,Ducluzeau Pierre Henri,Lip Gregory Y H,Fauchier Laurent
Diabetes, obesity & metabolism
AIM:To evaluate the associations between metabolically healthy obesity (MHO) and different types of incident cardiovascular events in a contemporary population. MATERIALS AND METHODS:All patients discharged from French hospitals in 2013 with at least 5 years of follow-up and without a history of major adverse cardiovascular event (MACE; myocardial infarction, heart failure [HF], ischaemic stroke or cardiovascular death [MACE-HF]) or underweight/malnutrition were identified. They were categorized by phenotypes defined by obesity and three metabolic abnormalities (diabetes, hypertension and hyperlipidaemia). Hazard ratios (HRs) for cardiovascular events during follow-up were adjusted on age, sex and smoking status at baseline. RESULTS:In total, 2 873 039 individuals were included in the analysis, among whom 272 838 (9.5%) had obesity. During a mean follow-up of 4.9 years, when pooling men and women, individuals with MHO had a higher risk of MACE-HF (multivariate-adjusted HR 1.22, 95% confidence interval [CI]: 1.19-1.24), new-onset HF (HR 1.34, 95% CI 1.31-1.37) and atrial fibrillation (AF; HR 1.33, 95% CI 1.30-1.37) compared with individuals with no obesity and zero metabolic abnormalities. By contrast, risks were not higher for myocardial infarction (HR 0.92, 95% CI 0.87-0.98), ischaemic stroke (HR 0.93, 95% CI 0.88-0.98) and cardiovascular death (HR 0.99, 95% CI 0.93-1.04). MHO in men was associated with a higher risk of clinical events compared with metabolically healthy men of normal weight (HR 1.12-1.80), while women with MHO had a lower risk for most events than metabolically healthy women of normal weight (HR 0.49-0.99). CONCLUSIONS:In a large and contemporary analysis of patients seen in French hospitals, individuals with MHO did not have a higher risk of myocardial infarction, ischaemic stroke or cardiovascular death than metabolically healthy individuals with no obesity. By contrast, they had a higher risk of new-onset HF and new-onset AF. However, notable differences were observed in men and women in the sex-stratified analysis.
Obesity and sleep disturbances: The "chicken or the egg" question.
Rodrigues Gabriel Dias,Fiorelli Elisa M,Furlan Ludovico,Montano Nicola,Tobaldini Eleonora
European journal of internal medicine
Obesity and sleep disturbances are common conditions in modern societies and accumulating evidence support a close bidirectional causal relationship between these two conditions. Indeed, from one side sleep loss seems to affect energy intake and expenditure through its direct effects on hormone-mediated sensations of satiety and hunger and through the influence on hedonic and psychological aspects of food consumption. Sleep deprived patients have been shown to experiment excessive daytime sleepiness, fatigue, and tiredness that, in a vicious circle, enhances physical inactivity and weight gain. On the other side, obesity is a well-known risk factor for several sleep disorders. This narrative review will discuss the main pathophysiological mechanisms that link sleep loss to obesity and metabolic syndrome with particular attention to the three most common sleep disorders (insomnia, obstructive sleep apnoea syndrome, restless leg syndrome).
Sex hormones regulate metainflammation in diet-induced obesity in mice.
Varghese Mita,Griffin Cameron,Abrishami Simin,Eter Leila,Lanzetta Nicholas,Hak Layla,Clemente Jeremy,Agarwal Devyani,Lerner Arianna,Westerhoff Maria,Patel Ravi,Bowers Emily,Islam Mohammed,Subbaiah Perla,Singer Kanakadurga
The Journal of biological chemistry
Men have a statistically higher risk of metabolic and cardiovascular disease than premenopausal women, but the mechanisms mediating these differences are elusive. Chronic inflammation during obesity contributes to disease risk and is significantly more robust in males. Prior work demonstrated that compared with obese males, obese females have reduced proinflammatory adipose tissue macrophages (ATMs). Given the paucity of data on how sex hormones contribute to macrophage responses in obesity, we sought to understand the role of sex hormones in promoting obesity-induced myeloid inflammation. We used gonadectomy, estrogen receptor-deficient alpha chimeras, and androgen-insensitive mice to model sex hormone deficiency. These models were evaluated in diet-induced obesity conditions (high-fat diet [HFD]) and in vitro myeloid assays. We found that ovariectomy increased weight gain and adiposity. Ovariectomized females had increased ATMs and bone marrow myeloid colonies compared with sham-gonadectomized females. In addition, castrated males exposed to HFD had improved glucose tolerance, insulin sensitivity, and adiposity with fewer Ly6c monocytes and bone marrow myeloid colonies compared with sham-gonadectomized males, although local adipose inflammation was enhanced. Similar findings were observed in androgen-insensitive mice; however, these mice had fewer CD11c ATMs, implying a developmental role for androgens in myelopoiesis and adipose inflammation. We concluded that gonadectomy results in convergence of metabolic and inflammatory responses to HFD between the sexes, and that myeloid estrogen receptor alpha contributes minimally to diet-induced inflammatory responses, whereas loss of androgen-receptor signaling improves metabolic and inflammatory outcomes. These studies demonstrate that sex hormones play a critical role in sex differences in obesity, metabolic dysfunction, and myeloid inflammation.
Sweet taste and obesity.
Ribeiro Gabriela,Oliveira-Maia Albino J
European journal of internal medicine
For more than 50 years, there has been evidence for greater consumption of sweet- foods in overweight humans and animals, relative to those that have a normal weight. Furthermore, it has long been suggested that energy deficit resulting from dieting, while moving the individual from a higher weight set point, would result in heightened susceptibility to palatable tastants, namely to sweet tastants. This was the motivation behind the first studies comparing sweet taste perception between individuals with obesity and those of a normal weight. These studies, using direct measures of taste, have been characterized by significant methodological heterogeneity, contributing towards variability in results and conclusions. Nevertheless, some of these findings have been used to support the theory that patients with obesity have decreased taste perception, particularly for sweet tastants. A similar hypothesis has been proposed regarding evidence for reduced brain dopamine receptors in obesity and, in both cases, it is proposed that increased food consumption, and associated weight gain, result from the need to increase sensory and brain stimulation. However, the available literature is not conclusive on the association between obesity and reduced sweet taste perception, with both negative and contradictory findings in comparisons between individuals with obesity and normal weight control subjects, as well as within-subject comparisons before and after bariatric surgery. Nevertheless, following either Roux-en-Y gastric bypass or sleeve gastrectomy, there is evidence of changes in taste perception, particularly for reward-related measures of sweet tastants, that should be further tested and confirmed in large samples, using consensual methodology.
Polysaccharides from mulberry (Morus alba L.) leaf prevents obesity by inhibiting pancreatic lipase in high-fat diet induced mice.
Li Ruilin,Xue Zihan,Jia Yanan,Wang Yajie,Li Shuqin,Zhou Jingna,Liu Junyu,Zhang Min,He Chengwei,Chen Haixia
International journal of biological macromolecules
Pancreatic lipase (PL) is a key enzyme related to the prevention and treatment of obesity. The aim of the study was to evaluate the inhibitory effects of mulberry leaf polysaccharides (MLP) on PL and possible interaction mechanism, inhibition on lipid accumulation in vitro and in vivo. The results revealed that MLP had obvious inhibitory effects on PL (P < 0.05). The interaction of MLP-PL complexes was in a spontaneous way driven by enthalpy, and hydrogen bonds were the main factors in the binding. MLP could significantly inhibit the development of lipid accumulation in HepG2 cells (P < 0.05). Furthermore, consumption of high-fat diet containing MLP showed protective effects on liver and adipose tissue damages in mice, and inhibited the lipid absorption in digestive tract. MLP also significantly reduced the increased expression level of pancreatic digestive enzymes (P < 0.05). The study indicated that the anti-obesity effect of MLP might be caused by inhibition of lipid absorption via reducing PL activity.
Transcriptional characterization of subcutaneous adipose tissue in obesity affected women highlights metabolic dysfunction and implications for lncRNAs.
Rey Federica,Messa Letizia,Pandini Cecilia,Barzaghini Bianca,Micheletto Giancarlo,Raimondi Manuela Teresa,Bertoli Simona,Cereda Cristina,Zuccotti Gian Vincenzo,Cancello Raffaella,Carelli Stephana
Obesity is a complex disease with multifactorial causes, and its prevalence is becoming a serious health crisis. For this reason, there is a crucial need to identify novel targets and players. With this aim in mind, we analyzed via RNA-sequencing the subcutaneous adipose tissue of normal weight and obesity-affected women, highlighting the differential expression in the two tissues. We specifically focused on long non-coding RNAs, as 6 of these emerged as dysregulated in the diseased-tissue (COL4A2-AS2, RPS21-AS, PELATON, ITGB2-AS1, ACER2-AS and CTEPHA1). For each of them, we performed both a thorough in silico dissection and in vitro validation, to predict their function during adipogenesis. We report the lncRNAs expression during adipose derived stem cells differentiation to adipocytes as model of adipogenesis and their potential modulation by adipogenesis-related transcription factors (C/EBPs and PPARγ). Moreover, inhibiting CTEPHA1 expression we investigated its impact on adipogenesis-related transcription factors, showing its significative dysregulation of C/EBPα expression. Lastly, we dissected the subcellular localization, pathway involvement and disease-correlation for coding differentially expressed genes. Together, these findings highlight a transcriptional deregulation at the basis of obesity, impacted by both coding and long non-coding RNAs.
GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity.
Prabata Adam,Ikeda Koji,Rahardini Elda Putri,Hirata Ken-Ichi,Emoto Noriaki
The Journal of biological chemistry
Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.
Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout.
Adams Charleen D,Boutwell Brian B
Observational studies suggest relationships between obesity, urate, and gout but are possibly confounded. We assessed whether genetically determined obesity, higher urate (and related traits), and gout were causal using multiple Mendelian randomization (MR) approaches and linkage disequilibrium score regression for genetic correlations (r). For data, we used genome-wide association study summary statistics available through MR-Base. We observed that obesity increased urate (beta = 0.127; 95% CI = 0.098, 0.157; P-value = 1.2E-17; r = 0.25 [P-value = 0.001]) and triglycerides (beta = 0.082; 95% CI = 0.065, 0.099; P-value = 1.2E-21; r = 0.23 [P-value = 8.8E-12]) and decreased high-density lipoprotein cholesterol (HDL) (beta = - 0.083; 95% CI = - 0.101, - 0.065; P-value = 2.5E-19; r = - 0.28; [P-value = 5.2E-24]). Higher triglycerides increased urate (beta = 0.198; 95% CI = 0.146, 0.251; P-value = 8.9E-14; r = 0.29 [P-value = 0.001]) and higher HDL decreased urate (beta = - 0.109; 95% CI = - 0.148, - 0.071; P-value = 2.7E- 08; r = - 0.21 [P-value = 9.8E-05]). Higher urate (OR = 1.030; 95% CI = 1.028, 1.032; P-value = 1.1E-130; r = 0.89 [P-value = 1.7E-55]) and obesity caused gout (OR = 1.003; 95% CI = 1.001, 1.004; P-value = 1.3E-04; r = 0.23 [P-value = 2.7E-05]). Obesity on gout with urate as a mediator revealed all the effect of obesity on gout occurred through urate. Obesity on low-density lipoprotein cholesterol (LDL) was null (beta = -0.011; 95% CI = -0.030, 0.008; P-value = 2.6E-01; r = 0.03 [P-value = 0.369]). A multivariable MR of obesity, HDL, and triglycerides on urate showed obesity influenced urate when accounting for HDL and triglycerides. Obesity's impact on urate was exacerbated by it decreasing HDL.
A systematic review of economic evaluations of web-based or telephone-delivered interventions for preventing overweight and obesity and/or improving obesity-related behaviors.
Brown Vicki,Tran Huong,Downing Katherine L,Hesketh Kylie D,Moodie Marj
Obesity reviews : an official journal of the International Association for the Study of Obesity
Obesity prevention interventions with behavioral or lifestyle-related components delivered via web-based or telephone technologies have been reported as comparatively low cost as compared with other intervention delivery modes, yet to date, no synthesized evidence of cost-effectiveness has been published. This study aimed to conduct a systematic review of economic evaluations of obesity prevention interventions with a telehealth or eHealth intervention component. A systematic search of six academic databases was conducted through October 2020. Studies were included if they reported full economic evaluations of interventions aimed at preventing overweight or obesity, or interventions aimed at improving obesity-related behaviors, with at least one intervention component delivered by telephone (telehealth) or web-based technology (eHealth). Findings were reported narratively, based on the Consolidated Health Economic Evaluation Reporting Standards. Twenty-seven economic evaluations were included from 20 studies meeting the inclusion criteria. Sixteen of the included interventions had a telehealth component, whereas 11 had an eHealth component. Seventeen interventions were evaluated using cost-utility analysis, five with cost-effectiveness analysis, and five undertook both cost-effectiveness and cost-utility analyses. Only eight cost-utility analyses reported that the intervention was cost-effective. Comparison of results from cost-effectiveness analyses was limited by heterogeneity in methods and outcome units reported. The evidence supporting the cost-effectiveness of interventions with a telehealth or eHealth delivery component is currently inconclusive. Although obesity prevention telehealth and eHealth interventions are gaining popularity, more evidence is required on their effectiveness and cost-effectiveness.
Obesity and responsibility: Is it time to rethink agency?
Grannell Andrew,Fallon Finian,Al-Najim Werd,le Roux Carel
Obesity reviews : an official journal of the International Association for the Study of Obesity
Despite obesity declared a disease, there still exists considerable weight stigma in both popular culture and health care, which negatively impacts policy making regarding prevention and treatment. While viewed as a choice or a failure of willpower by many, evidence exists to challenge the argument that both weight gain and failure to achieve weight loss maintenance are the individuals' fault due to personal failure or lack of responsibility. In this article, we draw upon literature from obesity treatment, neuroscience, philosophy of mind, and weight stigma to challenge the commonly held beliefs that individuals are free to choose how much they can weigh, and achievement of long-term weight loss maintenance is completely subject to conscious choice. In reality, the regulation of hunger, satiety, energy balance, and body weight takes place in subcortical regions of the brain. Thus, hunger and satiety signals are generated in regions of the brain, which are not associated with conscious experience. This points towards biological determinism of weight and challenges ideas of willpower and resultant moralization regarding body weight regulation. In this article, we will thus argue that in the context of dysregulation of hunger and satiety contributing to the obesity epidemic, a wider discourse related to personal responsibility and the stigma of obesity is needed to enhance understanding, prevention, and treatment of this complex disease. Obesity is a chronic disease requiring personalized treatment. Lifestyle interventions alone may not be enough to achieve medically significant and sustained weight loss for many individuals with obesity. By understanding that obesity is not due to a lack of motivation or willpower, the availability and utilization of additional treatments or combination of treatments such as lifestyle, pharmacotherapy, and surgery are likely to improve the quality of life for many suffering with this disease.
Physical exercise consequences on memory in obesity: A systematic review.
De Sousa Ricardo Augusto Leoni,Santos Letícia Gomes,Lopes Paulo Maurício,Cavalcante Bruno Raphael Ribeiro,Improta-Caria Alex Cleber,Cassilhas Ricardo Cardoso
Obesity reviews : an official journal of the International Association for the Study of Obesity
Obesity is associated with changes in memory. Thus, the aim of this systematic review was to investigate the physical exercise consequences on memory in obesity. A search was carried out in the PubMed, Lilacs, and Scielo databases with the following descriptors: "physical exercise," "memory," and "obesity." A total of 16 studies were analyzed in this review. Low, moderate, and high intensity exercise training showed positive effects on memory in patients with obesity (100%). The animal models of obesity used in their physical exercise protocols: treadmill (72.7%) or wheel running (27.3%). Most of the animal studies (81.8%) revealed positive effects of the physical exercise protocol on memory in obesity. Mouse was the most commonly used animal (54.5%), and a 60% high-fat diet (HFD) was the most commonly method used to induce obesity (82%). We did not identify any knockout model of obesity that was used to evaluate memory and used physical exercise as the main intervention. Thus, exercise training, independently if it is resistance or endurance training, seems to be an excellent intervention to prevent and inhibit cognitive impairment and memory loss on obese patients and animal models of obesity.
Patient initiation and maintenance of GLP-1 RAs for treatment of obesity.
Patel Dhiren,Smith April
Expert review of clinical pharmacology
Healthcare providers (HCPs) see many patients with obesity-related complications and are therefore well placed to help treat obesity itself. However, limited collated information exists to help HCPs with the practical use of anti-obesity medications (AOMs). We focus on the initiation and maintenance of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) for weight management, liraglutide 3.0 mg. Literature search was conducted between 25-28 November 2019 on PubMed and ClinicalTrials.gov. Clinical trial and real-world data describing weight-loss efficacy, cardiometabolic risk factors, incidence of adverse events (AEs), and persistence are presented to assist HCPs with patient discussions. Practical considerations to overcome barriers to optimal use are provided, equipping HCPs with the information required to aid with adherence to and persistence with AOMs. The use of other GLP-1- RA therapies in obesity is discussed in light of the recent US Food and Drug Administration approval of semaglutide 2.4 mg for weight management. Liraglutide 3.0 mg provides benefits regarding weight loss and improvements in cardiometabolic risk factors. Promising areas of future research in the field of obesity include dual receptor agonists and the combination of glucagon-like peptide-1 receptor agonists with other molecules.
LMO3 reprograms visceral adipocyte metabolism during obesity.
Wagner Gabriel,Fenzl Anna,Lindroos-Christensen Josefine,Einwallner Elisa,Husa Julia,Witzeneder Nadine,Rauscher Sabine,Gröger Marion,Derdak Sophia,Mohr Thomas,Sutterlüty Hedwig,Klinglmüller Florian,Wolkerstorfer Silviya,Fondi Martina,Hoermann Gregor,Cao Lei,Wagner Oswald,Kiefer Florian W,Esterbauer Harald,Bilban Martin
Journal of molecular medicine (Berlin, Germany)
Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity. KEY MESSAGES: LMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo. LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes. LMO3 increases nuclear coactivator 1 (Ncoa1). LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.
Children with Severe Obesity in Family-Based Obesity Treatment Compared with Other Participants: Conclusions Depend on Metrics.
Hayes Jacqueline F,Fowler Lauren A,Balantekin Katherine N,Saelens Brian E,Stein Richard I,Perri Michael G,Welch R Robinson,Epstein Leonard H,Wilfley Denise E
Obesity (Silver Spring, Md.)
OBJECTIVE:This study compares children with severe obesity and children with mild obesity/overweight participating in family-based obesity treatment (FBT) on change in (1) relative weight and adiposity and (2) psychosocial distress. METHODS:Children 7 to 11 years old (N = 241) and their parents participated in 12 months of behavioral treatment (FBT + maintenance treatment) and completed anthropometric, adiposity, and psychosocial assessments (psychiatric disorder symptomology, quality of life). Severe obesity was defined as a baseline BMI ≥ 120% of the 95th percentile (N = 105). RESULTS:At 12 months, 40% of children with baseline severe obesity no longer had severe obesity. Percent overweight and fat mass index measurements showed similar magnitudes of change among children with severe obesity and children with mild obesity/overweight, whereas BMI z score and percent body fat change was lower in the group with severe obesity. Youth with severe obesity were higher on some measures of psychosocial distress at baseline but generally experienced improvements similar to children with mild obesity/overweight. CONCLUSIONS:FBT with maintenance treatment is beneficial for children with severe obesity and is recommended for use prior to more invasive treatments in severe pediatric obesity. Future studies should assess the necessity of additional treatment, as children with severe obesity still have high relative weights post intervention.
The Impact of Obesity on Critical Illnesses.
Ayalon Itay,Bodilly Lauren,Kaplan Jennifer
Shock (Augusta, Ga.)
ABSTRACT:In the last few decades, obesity became one of the world's greatest health challenges reaching a size of global epidemic in virtually all socioeconomic statuses and all age groups. Obesity is a risk factor for many health problems and as its prevalence gradually increases is becoming a significant economic and health burden. In this manuscript we describe how normal respiratory and cardiovascular physiology is altered by obesity. We review past and current literature to describe how obesity affects outcomes of patients facing critical illnesses and discuss some controversies related to this topic.
Weight stigma and obesity-related policies: A systematic review of the state of the literature.
Hill Briony,Bergmeier Heidi,Incollingo Rodriguez Angela C,Barlow Fiona Kate,Chung Alexandra,Ramachandran Divya,Savaglio Melissa,Skouteris Helen
Obesity reviews : an official journal of the International Association for the Study of Obesity
Weight stigma is an important issue colliding with obesity-related policies; both have population health and social impacts. Our aim was to conduct a systematic review of the peer-reviewed literature that combined the concepts of stigma, obesity, and policy. We searched PsycINFO, Medline, Scopus, and Google Scholar for peer-reviewed articles amalgamating terms relevant to stigma, obesity, and policy. Of 3219 records identified, 47 were included in the narrative synthesis. Two key types of studies emerged: studies investigating factors associated with support for obesity-related policies and those exploring policy implementation and evaluation. We found that support for nonstigmatizing obesity-related policies was higher when obesity was attributed as an environmental rather than individual problem. An undercurrent theme suggested that views that blame individuals for their obesity were associated with support for punitive policies for people living in larger bodies. Real-world policies often implicitly condoned stigma through poor language choice and conflicting discourse. Our findings inform recommendations for policy makers that broader socioecological stigma-reduction approaches are needed to fully address the issue of weight stigma in obesity-related policies. Efforts are needed in the research and policy sectors to understand how to improve the design and support of nonstigmatizing obesity-related policies.
Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation.
Yao Jingfei,Wu Dongmei,Zhang Chunyan,Yan Ting,Zhao Yiheng,Shen Hongyu,Xue Kaili,Huang Xun,Wang Zihao,Qiu Yifu
Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.
Endocrine-disrupting chemicals and obesity risk: A review of recommendations for obesity prevention policies.
Lobstein Tim,Brownell Kelly D
Obesity reviews : an official journal of the International Association for the Study of Obesity
Emerging evidence indicates that industrially produced endocrine-disrupting chemicals (EDCs) may be as obesogenic as poor dietary patterns and should be considered in obesity prevention policies. The authors conducted two reviews: (a) a systematic search of four electronic databases for papers published since January 2010 to identify the policy recommendations contained in scientific reviews of EDC exposure and obesity risk and (b) a narrative review of obesity policy documents published since January 2012 to identify the recommendations of national and international agencies. A search of four electronic databases found 63 scientific reviews with policy recommendations, of which 26 suggested individual responsibility to avoid exposure, 11 suggested medical interventions to counter the effects of exposure, and 42 suggested regulatory control of hazardous chemicals. Of sixty policy documents examined, six mentioned pollutants as a possible risk factor for obesity, and only one made explicit reference to strategies for reducing exposure to EDCs. The UN Sustainable Development Goals include targets to prevent ill health from hazardous chemicals (Targets 3.9 and 12.4) and to remove unsafe industrial chemicals from the environment (Targets 6.3, 11.6, 12.4, and 14.1). The authors suggest these should be explicitly linked to World Health Assembly targets to halt the rise in obesity.
Synergizing Mouse and Human Studies to Understand the Heterogeneity of Obesity.
Gordon-Larsen Penny,French John E,Moustaid-Moussa Naima,Voruganti Venkata S,Mayer-Davis Elizabeth J,Bizon Christopher A,Cheng Zhiyong,Stewart Delisha A,Easterbrook John W,Shaikh Saame Raza
Advances in nutrition (Bethesda, Md.)
Obesity is routinely considered as a single disease state, which drives a "one-size-fits-all" approach to treatment. We recently convened the first annual University of North Carolina Interdisciplinary Nutrition Sciences Symposium to discuss the heterogeneity of obesity and the need for translational science to advance understanding of this heterogeneity. The symposium aimed to advance scientific rigor in translational studies from animal to human models with the goal of identifying underlying mechanisms and treatments. In this review, we discuss fundamental gaps in knowledge of the heterogeneity of obesity ranging from cellular to population perspectives. We also advocate approaches to overcoming limitations in the field. Examples include the use of contemporary mouse genetic reference population models such as the Collaborative Cross and Diversity Outbred mice that effectively model human genetic diversity and the use of translational models that integrate -omics and computational approaches from pre-clinical to clinical models of obesity. Finally, we suggest best scientific practices to ensure strong rigor that will allow investigators to delineate the sources of heterogeneity in the population with obesity. Collectively, we propose that it is critical to think of obesity as a heterogeneous disease with complex mechanisms and etiologies, requiring unique prevention and treatment strategies tailored to the individual.
Genetics of Sleep and Insights into Its Relationship with Obesity.
Dashti Hassan S,Ordovás José M
Annual review of nutrition
Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the involvement of the circadian clock in sleep and metabolism, few shared genes, including , were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring. Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. In addition, bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity,but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited.
A systematic literature review on obesity: Understanding the causes & consequences of obesity and reviewing various machine learning approaches used to predict obesity.
Safaei Mahmood,Sundararajan Elankovan A,Driss Maha,Boulila Wadii,Shapi'i Azrulhizam
Computers in biology and medicine
Obesity is considered a principal public health concern and ranked as the fifth foremost reason for death globally. Overweight and obesity are one of the main lifestyle illnesses that leads to further health concerns and contributes to numerous chronic diseases, including cancers, diabetes, metabolic syndrome, and cardiovascular diseases. The World Health Organization also predicted that 30% of death in the world will be initiated with lifestyle diseases in 2030 and can be stopped through the suitable identification and addressing of associated risk factors and behavioral involvement policies. Thus, detecting and diagnosing obesity as early as possible is crucial. Therefore, the machine learning approach is a promising solution to early predictions of obesity and the risk of overweight because it can offer quick, immediate, and accurate identification of risk factors and condition likelihoods. The present study conducted a systematic literature review to examine obesity research and machine learning techniques for the prevention and treatment of obesity from 2010 to 2020. Accordingly, 93 papers are identified from the review articles as primary studies from an initial pool of over 700 papers addressing obesity. Consequently, this study initially recognized the significant potential factors that influence and cause adult obesity. Next, the main diseases and health consequences of obesity and overweight are investigated. Ultimately, this study recognized the machine learning methods that can be used for the prediction of obesity. Finally, this study seeks to support decision-makers looking to understand the impact of obesity on health in the general population and identify outcomes that can be used to guide health authorities and public health to further mitigate threats and effectively guide obese people globally.
GLP-1 physiology informs the pharmacotherapy of obesity.
Drucker Daniel J
BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity. SCOPE OF REVIEW:Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system is outlined, and the importance of pathways controlling energy expenditure in preclinical studies, vs. reduction of food intake in both animals and humans, is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for physiological reduction of food intake and the anorectic response to GLP1RA is compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy, liraglutide 3 mg daily and semaglutide 2.4 mg once weekly, is discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed dose combination therapies, are highlighted. MAJOR CONCLUSIONS:The actions of GLP-1 to reduce food intake and body weight are highly conserved in animals and humans, in both adolescents and adults, with obesity. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.
Nutrition and cellular senescence in obesity-related disorders.
Rubio-Tomás Teresa,Rueda-Robles Ascensión,Plaza-Díaz Julio,Álvarez-Mercado Ana I
The Journal of nutritional biochemistry
Adequate nutrition is vital for immune homeostasis. However, the incidence of obesity is increasing worldwide due to the adoption of the Western diet and a sedentary lifestyle. Obesity is associated with chronic inflammation which alters the function of adipose tissue, liver, pancreas, and the nervous system. Inflammation is related to cellular senescence, distinguished by irreversible cell cycle arrest. Senescent cells secrete the senescence-associated secretory phenotype (SASP) which contains pro-inflammatory factors. Targeting processes in senescence might have a salutary approach to obesity. The present review highlights the impact of an unhealthy diet on tissues affected by obesity, and the mechanisms that promote the consequent inflammation and senescence.
Vascular reactivity contributes to adipose tissue remodeling in obesity.
Lee Hye-Jin,Shi Haifei,Brönneke Hella S,Jin Bo-Yeong,Choi Sang-Hyun,Seeley Randy J,Kim Dong-Hoon
The Journal of endocrinology
Vascular reactivity of adipose tissue (AT) is hypothesized to play an important role in the development of obesity. However, the exact role of vascular reactivity in the development of obesity remains unclear. In this study, we investigated the chronological changes in vascular reactivity and the microenvironments of the visceral AT (VAT) and subcutaneous AT (SAT) in lean and obese mice. Changes in blood flow levels induced by a β-adrenoceptor agonist (isoproterenol) were significantly lower in the VAT of the mice fed a high-fat diet (HFD) for 1 and 12 weeks, compared to those in the VAT of the mice fed a low-fat diet (LFD) for the same period; no significant change was observed in the SAT of any mouse group, suggesting depot-specific vascular reactivity of AT. Consistently, the hypoxic area and the expression of genes associated with angiogenesis and macrophage recruitment were increased in the VAT (but not in the SAT) of mice fed an HFD for 1 week, compared with mice fed an LFD. These changes occurred with no morphological changes, including those related to adipocyte size, AT vessel density, and the diameter and pericyte coverage of the endothelium, suggesting a determinant role of vascular reactivity in the type of AT remodeling. The suppression of vascular reactivity was accompanied by increased endothelin-1 gene expression and extracellular matrix (ECM) stiffness only in the VAT, implying enhanced contractile activities of the vasculature and ECM. The results suggest a depot-specific role of vascular reactivity in AT remodeling during the development of obesity.
Sex/Gender Differences in Obesity Prevalence, Comorbidities, and Treatment.
Cooper Ashley J,Gupta Sapana R,Moustafa Afaf F,Chao Ariana M
Current obesity reports
PURPOSE OF REVIEW:Obesity is a heterogeneous condition, yet sex/gender is rarely considered in the prevention or clinical care of this disease. This review examined and evaluated recent literature regarding the influence of sex and gender on obesity prevalence, comorbidities, and treatment in adults. RECENT FINDINGS:Obesity is more prevalent in women than men in most countries, but in some countries and population subgroups, this gap is more pronounced. Several obesity-related comorbidities, including type 2 diabetes and hypertension, demonstrate sex-specific pathways. Women, compared to men, are more likely to be diagnosed with obesity and seek and obtain all types of obesity treatment including behavioral, pharmacological, and bariatric surgery. Men tend to have greater absolute weight loss, but this difference is attenuated once accounting for baseline weight. Obesity is a multifactorial condition with complex interactions among sex/gender, sociocultural, environmental, and physiological factors. More sex/gender research is needed to investigate mechanisms underlying sex/gender differences in prevalence, comorbidities, and treatment, identify ways to increase men's interest and participation in obesity treatment, and examine differences in obesity prevalence and treatments for transgender and gender non-conforming individuals.
Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce.
Li Qian,Hagberg Carolina E,Silva Cascales Helena,Lang Shuai,Hyvönen Mervi T,Salehzadeh Firoozeh,Chen Ping,Alexandersson Ida,Terezaki Eleni,Harms Matthew J,Kutschke Maria,Arifen Nahida,Krämer Niels,Aouadi Myriam,Knibbe Carole,Boucher Jeremie,Thorell Anders,Spalding Kirsty L
Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation.
The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity.
Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the brain. The brain is capable of regulating both energy intake and expenditure and plays a critical role in human obesity. In addition, the GIP receptor is widely distributed throughout the brain, including areas responsible for energy homeostasis. Recent studies have uncovered previously underappreciated roles of the GIP receptor in the brain in the context of obesity. This article highlights how the GIP receptor expressed by the brain impacts obesity-related pathogenesis.
Help or hindrance: The obesity paradox in cancer treatment response.
O'Connell Fiona,O'Sullivan Jacintha
Obesity is a rising epidemic, the influence of which on cancer development, progression as well as its impact on current standard of care cancer treatments is profound with many facets. Obesity is emerging as a modulating factor in many cancer therapies, such as chemotherapy, radiotherapy, immunotherapy and combination therapies. It has been reported to diminish the efficacy of some treatments but has also been alluded to being protective in terms of reduced treatment toxicities, thus the evolution of the obesity paradox. The obese tumour microenvironment influences treatment response through modulation of a series of aspects, including altered adipocyte secretome, angiogenesis, hypoxia, fibrosis, free fatty acid uptake as well as a modulated immune landscape. However, the influence of these underlying mechanisms on cancer treatment response and the biological action of adipose tissue is still largely unknown. Elucidation of these facets may lead to the enhanced efficacy of current treatment options or the identification of novel methods to combat cancer in the obese tumour microenvironment.
Does Modern Lifestyle Favor Neuroimmunometabolic Changes? A Path to Obesity.
Marques Camila Guazzelli,Dos Santos Quaresma Marcus V L,Nakamoto Fernanda Patti,Magalhães Ana Carolina Oumatu,Lucin Glaice Aparecida,Thomatieli-Santos Ronaldo Vagner
Frontiers in nutrition
Factors linked to modern lifestyles, such as physical inactivity, Western diet, and poor sleep quality have been identified as key contributors to the positive energy balance (PEB). PEB rises adipose tissue hypertrophy and dysfunction over the years, affecting cells and tissues that are metabolically critical for energy homeostasis regulation, especially skeletal muscle, hypothalamic-pituitary-adrenal axis, and gut microbiota. It is known that the interaction among lifestyle factors and tissue metabolic dysfunction increases low-grade chronic systemic inflammation, leading to insulin resistance and other adverse metabolic disorders. Although immunometabolic mechanisms are widely discussed in obesity, neuroimmunoendocrine pathways have gained notoriety, as a link to neuroinflammation and central nervous system disorders. Hypothalamic inflammation has been associated with food intake dysregulation, which comprises homeostatic and non-homeostatic mechanisms, promoting eating behavior changes related to the obesity prevalence. The purpose of this review is to provide an updated and integrated perspective on the effects of Western diet, sleep debt, and physical exercise on the regulation of energy homeostasis and low-grade chronic systemic inflammation. Subsequently, we discuss the intersection between systemic inflammation and neuroinflammation and how it can contribute to energy imbalance, favoring obesity. Finally, we propose a model of interactions between systemic inflammation and neuroinflammation, providing new insights into preventive and therapeutic targets for obesity.
Aging, obesity, sarcopenia and the effect of diet and exercise intervention.
Colleluori Georgia,Villareal Dennis T
The number of adults 65 years and older is increasing worldwide and will represent the 20% of the population by 2030. Half of them will suffer from obesity. The decline in muscle mass and strength, known as sarcopenia, is very common among older adults with obesity (sarcopenic obesity). Sarcopenic obesity is strongly associated with frailty, cardiometabolic dysfunction, physical disability, and mortality. Increasing efforts have been hence made to identify effective strategies able to promote healthy aging and curb the obesity pandemic. Among these, lifestyle interventions consisting of diet and exercise protocols have been extensively explored. Importantly, diet-induced weight loss is associated with fat, muscle, and bone mass losses, and may further exacerbate age-related sarcopenia and frailty outcomes in older adults. Successful approaches to induce fat mass loss while preserving lean and bone mass are critical to reduce the aging- and obesity-related physical and metabolic complications and at the same time ameliorate frailty. In this review article, we discuss the most recent evidence on the age-related alterations in adipose tissue and muscle health and on the effect of calorie restriction and exercise approaches for older adults with obesity and sarcopenia, emphasizing the existing gaps in the literature that need further investigation.
Dysregulated resting state functional connectivity and obesity: A systematic review.
Syan Sabrina K,McIntyre-Wood Carly,Minuzzi Luciano,Hall Geoffrey,McCabe Randi E,MacKillop James
Neuroscience and biobehavioral reviews
Obesity has been variously linked to differences in brain functional connectivity in regions associated with reward, emotional regulation and cognition, potentially revealing neural mechanisms contributing to its development and maintenance. This systematic review summarizes and critically appraises the existing literature on differences in resting state functional connectivity (Rs-FC) between overweight and individuals with obesity in relation healthy-BMI controls. Twenty-nine studies were identified and the results consistently support the hypothesis that obesity is associated with differences in Rs-FC. Specifically, obesity/overweight was consistently associated with (i) DMN hypoconnectivity and salience network hyperconnectivity; (ii) increased Rs-FC between the hypothalamus and reward, limbic and salience networks, and decreased Rs-FC between the hypothalamus and cognitive regions; (iii) increased power within regions associated with inhibition/emotional reasoning; (iv) decreased nodal efficiency, degree centrality, and global efficiency. Collectively, the results suggest obesity is associated with disrupted connectivity of brain networks responsible for cognition, reward, self-referential processing and emotional regulation.
Adipocyte NR1D1 dictates adipose tissue expansion during obesity.
Hunter Ann Louise,Pelekanou Charlotte E,Barron Nichola J,Northeast Rebecca C,Grudzien Magdalena,Adamson Antony D,Downton Polly,Cornfield Thomas,Cunningham Peter S,Billaud Jean-Noel,Hodson Leanne,Loudon Andrew Si,Unwin Richard D,Iqbal Mudassar,Ray David W,Bechtold David A
The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity.
O'Brien Conan J O,Haberman Emma R,Domingos Ana I
Annual review of cell and developmental biology
The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.
Obesity-Associated Mutations and the Melanocortin Pathway.
Mendes de Oliveira Edson,Keogh Julia M,Talbot Fleur,Henning Elana,Ahmed Rachel,Perdikari Aliki,Bounds Rebecca,Wasiluk Natalia,Ayinampudi Vikram,Barroso Inês,Mokrosiński Jacek,Jyothish Deepthi,Lim Sharon,Gupta Sanjay,Kershaw Melanie,Matei Cristina,Partha Praveen,Randell Tabitha,McAulay Antoinette,Wilson Louise C,Cheetham Tim,Crowne Elizabeth C,Clayton Peter,Farooqi I Sadaf
The New England journal of medicine
BACKGROUND: encodes the Gα (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS:We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 mutation carriers. We investigated whether the effect of mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS:Almost all mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS:Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).
Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice.
Mishra Sumita,Sadagopan Nandhini,Dunkerly-Eyring Brittany,Rodriguez Susana,Sarver Dylan C,Ceddia Ryan P,Murphy Sean A,Knutsdottir Hildur,Jani Vivek P,Ashok Deepthi,Oeing Christian U,O'Rourke Brian,Gangoiti Jon A,Sears Dorothy D,Wong G William,Collins Sheila,Kass David
The Journal of clinical investigation
Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) in both ovariectomized female or male mice suppresses pre-established severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure-load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat, stimulating mitochondrial activity in brown and white fat, and improving CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis and mitochondrial respiration in adipocytes and myocytes coupled to PPARα-dependent gene regulation. PPARα upregulation was required to achieve the lipolytic, anti-obesity, and metabolic effects of PDE9-I. All these PDE9-I induced changes were not observed in obese/CMS non-ovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was re-oriented away from fat-metabolism regulating genes when stimulated in the presence of co-activated estrogen receptor-alpha, and this may underly the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.
Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models.
Lindberg Iris,Fricker Lloyd D
Peptides derived from proopiomelanocortin (POMC) are well-established neuropeptides and peptide hormones that perform multiple functions, including regulation of body weight. In humans and some animals, these peptides include α- and β-melanocyte-stimulating hormone (MSH). In certain rodent species, no β-MSH is produced from POMC because of a change in the cleavage site. Enzymes that convert POMC into MSH include prohormone convertases (PCs), carboxypeptidases (CPs), and peptidyl-α-amidating monooxygenase (PAM). Humans and mice with inactivating mutations in either PC1/3 or carboxypeptidase E (CPE) are obese, which was assumed to result from defective processing of POMC into MSH. However, recent studies have shown that selective loss of either PC1/3 or CPE in POMC-expressing cells does not cause obesity. These findings suggest that defects in POMC processing cannot alone account for the obesity observed in global PC1/3 or CPE mutants. We propose that obesity in animals lacking PC1/3 or CPE activity depends, at least in part, on deficient processing of peptides in non-POMC-expressing cells either in the brain and/or the periphery. Genetic background may also contribute to the manifestation of obesity.
Potential role of anti-inflammatory HDL subclasses in metabolic unhealth/obesity.
Tang Hongjuan,Xiang Zhicong,Li Longyu,Shao Xiaofei,Zhou Qin,You Xu,Xiong Chongxiang,Ning Jing,Chen Tong,Deng David,Zou Hequn
Artificial cells, nanomedicine, and biotechnology
High-density lipoprotein (HDL) particles comprising heterogeneous subclasses of different functions exert anti-inflammatory effects by interacting with immune-response cells. However, the relationship of HDL subclasses with immune-response cells in metabolic unhealth/obesity has not been defined clearly. The purpose of this study was to delineate the relational changes of HDL subclasses with immune cells and inflammatory markers in metabolic unhealth/obesity to understand the role of anti-inflammatory HDL subclasses. A total of 316 participants were classified by metabolic health. HDL subclasses were detected by microfluidic chip electrophoresis. White blood cell (WBC) counts and lymphocytes were assessed using automatic haematology analyser. Levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) were measured. In our study, not only the distribution of HDL subclasses, but also HDL-related structural proteins changed with the deterioration of metabolic disease. Moreover, lymphocytes and inflammation factors significantly gradually increased. The level of HDL2b was negatively associated with WBC, lymphocytes and hs-CRP in multivariable linear regression analysis. In multinomial logistic regression analysis, high levels of HDL3 and low levels of HDL2b increased the probability of having an unfavourable metabolic unhealth/obesity status. We supposed that HDL2b particles may play anti-inflammation by negatively regulating lymphocytes activation. HDL2b may be a therapeutic target for future metabolic disease due to the anti-inflammatory effects.