Extracellular vesicles as signaling mediators in type 2 diabetes mellitus.
Noren Hooten Nicole,Evans Michele K
American journal of physiology. Cell physiology
Diabetes mellitus type 2, a chronic metabolic disease, has globally increased in incidence and prevalence throughout the lifespan due to the rise in obesity and sedentary lifestyle. The end-organ cardiovascular and cerebrovascular effects of diabetes mellitus result in significant morbidity and mortality that increases with age. Thus, it is crucial to fully understand how molecular mechanisms are influenced by diabetes mellitus and may influence the development of end-organ complications. Circulating factors are known to play important physiological and pathological roles in diabetes. Recent data have implicated extracellular vesicles (EVs) as being circulating mediators in type 2 diabetes. These small lipid-bound vesicles are released by cells into the circulation and can carry functional cargo, including lipids, proteins, and nucleic acids, to neighboring cells or between tissues. In this review, we will summarize the current evidence for EVs as promising diagnostic and prognostic factors in diabetes, the mechanisms that drive EV alterations with diabetes, and the role EVs play in the pathology associated with diabetes.
Molecular aspects of diabetes mellitus: Resistin, microRNA, and exosome.
Saeedi Borujeni Mohammad Javad,Esfandiary Ebrahim,Taheripak Gholamreza,Codoñer-Franch Pilar,Alonso-Iglesias Eulalia,Mirzaei Hamed
Journal of cellular biochemistry
Diabetes mellitus (DM) is known as one of important common endocrine disorders which could due to deregulation of a variety of cellular and molecular pathways. A large numbers studies indicated that various pathogenesis events including mutation, serin phosphorylation, and increasing/decreasing expression of many genes could contribute to initiation and progression of DM. Insulin resistance is one of important factors which could play critical roles in DM pathogenesis. It has been showed that insulin resistance via targeting a sequence of cellular and molecular pathways (eg, PI3 kinases, PPARγ co-activator-1, microRNAs, serine/threonine kinase Akt, and serin phosphorylation) could induce DM. Among of various factors involved in DM pathogenesis, microRNAs, and exosomes have been emerged as effective factors in initiation and progression of DM. A variety of studies indicated that deregulation of these molecules could change behavior of various types of cells and contribute to progression of DM. Resistin is other main factor which is known as signal molecule involved in insulin resistance. Multiple lines evidence indicated that resistin exerts its effects via affecting on glucose metabolism, inhibition of fatty acid uptake and metabolism with affecting on a variety of targets such as CD36, fatty acid transport protein 1, Acetyl-CoA carboxylase, and AMP-activated protein kinase. Here, we summarized various molecular aspects are associated with DM particularly the molecular pathways involved in insulin resistance and resistin in DM. Moreover, we highlighted exosomes and microRNAs as effective players in initiation and progression of DM.
Exosomes and diabetes.
Castaño Carlos,Novials Anna,Párrizas Marcelina
Diabetes/metabolism research and reviews
Diabetes is a group of metabolic diseases characterized by elevated blood glucose levels that drive the development of life-threatening complications. Diabetes results from a situation of insufficient insulin action, either by deficient production of the hormone by the pancreas, or by the development of insulin resistance in peripheral tissues such as liver, muscle, or the adipose depots. Communication between organs is thus central to the maintenance of glucose homoeostasis. Recently, several studies are evidencing that small vesicles called exosomes released by, amongst other, the adipose tissue can regulate gene expression in other tissues, hence modulating interorgan crosstalk. Therefore, exosomes participate in the development of diabetes and its associated complications. Their study holds the potential of providing us with novel biomarkers for the early diagnosis and stratification of patients at risk of developing diabetes, hence allowing the timely implementation of more personalized therapies. On the other hand, the molecular dissection of the pathways initiated by exosomes under situations of metabolic stress could help to gain a deeper knowledge of the pathophysiology of diabetes and its associated metabolic diseases.
Berberine attenuates podocytes injury caused by exosomes derived from high glucose-induced mesangial cells through TGFβ1-PI3K/AKT pathway.
Wang Ying-Ying,Tang Li-Qin,Wei Wei
European journal of pharmacology
Diabetic nephropathy is the most common microvascular complications of diabetes. Berberine is the main active ingredient of Coptis chinensis and previous studies have been showed that berberine could delay the progression of diabetic nephropathy by regulating related cytokines and signaling pathways. Glomerular mesangial cells and podocytes are two vital indigenous cells of kidney and interaction between these two cellular components via exosomes might affect function of glomerulus in diabetic nephropathy condition. On the basis of our previous studies, transwell systems were used to demonstrate that the exosomes released by glomerular mesangial cells induced by the high glucose were involved in podocytes injury. The current study demonstrates that berberine can reduce TGFβ1 in exosomes released by high glucose-induced glomerular mesangial cells. Berberine-treated high glucose-induced exosomes which are secreted by glomerular mesangial cells can protect damage of podocytes by reducing apoptosis and increasing adhesion. These results suggest that berberine could protect the function of podocytes through inhibiting the transfer of TGFβ1 from the glomerular mesangial cells to the podocytes, which is one of the potential mechanisms of protective effect of berberine on diabetic nephropathy.
Adipose-derived exosomes: A novel adipokine in obesity-associated diabetes.
Zhang Bo,Yang Yang,Xiang Lin,Zhao Zhihe,Ye Rui
Journal of cellular physiology
Dysfunction of the adipose tissue is a central driver for obesity-associated diabetes. It is characterized by dysregulated adipokine secretion, which contributes to insulin resistance of key metabolic tissues, including the liver, skeletal muscles, and fat itself. The inter-organ cross talk between the adipose tissue and the other organs as well as the intra-organ cross talk between adipocytes and macrophages within the adipose tissue, traditionally mediated by hormones, was recently evidenced to be regulated by adipose-derived exosomes. Exosomes are nano-sized membrane-bound vesicles secreted by the donor cells to modify intercellular communication by translating constituent nucleic acids and proteins to the target cells. Herein, we reviewed the latest progress in understanding the role of adipose-derived exosomes in the development of insulin resistance, a key mechanism that underpins diabetes and diabetic complications, with a special focus on the role of exosomal miRNAs (micro RNAs) and proteins, and discusses the potential implications of targeting adipose tissue-derived exosomes for diabetic therapeutics.
miR-210 in Exosomes Derived from Macrophages under High Glucose Promotes Mouse Diabetic Obesity Pathogenesis by Suppressing NDUFA4 Expression.
Journal of diabetes research
OBJECTIVE:Type 2 diabetes mellitus (T2DM) is featured by insulin resistance and lipid metabolism dysregulation. A large number of miRNAs were identified in exosomes derived from adipose tissue macrophages associated with T2DM pathogenesis, but its pathogenic roles remain unknown. This study is aimed at investigating the function of miR-210 in diabetic obesity. METHODS:Exosomes from mouse macrophage RAW264.7 cells were characterized by electron microscopy, combined with biomarker expression by western blot. Expression of miR-210 was determined by quantitative RT-PCR. Glucose uptake was measured by a fluorometric method, and the mitochondrial respiratory chain activity was evaluated by ELISA. The target gene of miR-210 was validated by dual-luciferase reporter and pull-down assays. A mouse obese diabetic model was established by a high-fat diet and streptozocin treatment. RESULTS:miR-210 was highly expressed in exosomes derived from high glucose-induced macrophage RAW264.7 cells. Macrophage-derived exosomes impaired glucose uptake and mitochondrial CIV complex activity and suppressed NADH dehydrogenase ubiquinone 1 alpha subcomplex 4 (NDUFA4) expression in 3T3-L1 adipocytes. miR-210 directly bind with mRNA sequences of NDUFA4 gene. Inhibition of miR-210 mitigated the effects of macrophage-derived exosomes on the glucose uptake and complex IV (CIV) activity in 3T3-L1 adipocytes, and NDUFA4 overexpression offset the inhibition of glucose uptake and CIV activity by macrophage-derived exosomes. Furthermore, mice with miR-210 knockout showed greatly repressed diabetic obesity development. CONCLUSION:miR-210 derived from adipose tissue macrophages promotes mouse obese diabetes pathogenesis by regulating glucose uptake and mitochondrial CIV activity through targeting NDUFA4 gene expression.
Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose Tissue.
Zhao Hui,Shang Qianwen,Pan Zhenzhen,Bai Yang,Li Zequn,Zhang Huiying,Zhang Qiu,Guo Chun,Zhang Lining,Wang Qun
Adipose-derived stem cells (ADSCs) play critical roles in controlling obesity-associated inflammation and metabolic disorders. Exosomes from ADSCs exert protective effects in several diseases, but their roles in obesity and related pathological conditions remain unclear. In this study, we showed that treatment of obese mice with ADSC-derived exosomes facilitated their metabolic homeostasis, including improved insulin sensitivity (27.8% improvement), reduced obesity, and alleviated hepatic steatosis. ADSC-derived exosomes drove alternatively activated M2 macrophage polarization, inflammation reduction, and beiging in white adipose tissue (WAT) of diet-induced obese mice. Mechanistically, exosomes from ADSCs transferred into macrophages to induce anti-inflammatory M2 phenotypes through the transactivation of arginase-1 by exosome-carried active STAT3. Moreover, M2 macrophages induced by ADSC-derived exosomes not only expressed high levels of tyrosine hydroxylase responsible for catecholamine release, but also promoted ADSC proliferation and lactate production, thereby favoring WAT beiging and homeostasis in response to high-fat challenge. These findings delineate a novel exosome-mediated mechanism for ADSC-macrophage cross talk that facilitates immune and metabolic homeostasis in WAT, thus providing potential therapy for obesity and diabetes.
Adipose-specific knockdown of results in obesity and insulin resistance by promoting exosomes release.
Li Fang,Li Huixia,Jin Xinxin,Zhang Ying,Kang Xiaomin,Zhang Zhuanmin,Xu Mao,Qian Zhuang,Ma Zhengmin,Gao Xin,Zhao Liting,Wu Shufang,Sun Hongzhi
Cell cycle (Georgetown, Tex.)
Sirtuin1 (SIRT1) has recently emerged as a pivotal regulator of glucose metabolism and insulin sensitivity. However, the underlying mechanism has not been fully elucidated. In this study, we investigated the role of SIRT1 in the development of obesity and insulin resistance by generating mice with adipose-specific ablation of (Ad- mice). Ad- mice exhibited increased fat mass, impaired glucose tolerance, attenuated insulin sensitivity, and increased exosomes, whereas the administration of exosomes inhibitor effectively ameliorated the impaired metabolic profile in Ad- mice. Moreover, the increased exosomes were proved to be a result of defective autophagy activity in Ad- mice and restoration of SIRT1 activity efficiently improved metabolic profiles . Further study demonstrated that deficiency-induced exosomes modulated insulin sensitivity at least partially via the TLR4/NF-κB signaling pathway. Therefore, our findings implicated SIRT1 as a key factor in metabolic regulation, and adipose deficiency could exert an effect on the development of obesity and insulin resistance by promoting exosome release.
Role of exosome-associated microRNA in diagnostic and therapeutic applications to metabolic disorders.
Yao Zhen-Yu,Chen Wen-Bin,Shao Shan-Shan,Ma Shi-Zhan,Yang Chong-Bo,Li Meng-Zhu,Zhao Jia-Jun,Gao Ling
Journal of Zhejiang University. Science. B
Metabolic disorders are classified clinically as a complex and varied group of diseases including metabolic syndrome, obesity, and diabetes mellitus. Fat toxicity, chronic inflammation, and oxidative stress, which may change cellular functions, are considered to play an essential role in the pathogenetic progress of metabolic disorders. Recent studies have found that cells secrete nanoscale vesicles containing proteins, lipids, nucleic acids, and membrane receptors, which mediate signal transduction and material transport to neighboring and distant cells. Exosomes, one type of such vesicles, are reported to participate in multiple pathological processes including tumor metastasis, atherosclerosis, chronic inflammation, and insulin resistance. Research on exosomes has focused mainly on the proteins they contain, but recently the function of exosome-associated microRNA has drawn a lot of attention. Exosome-associated microRNAs regulate the physiological function and pathological processes of metabolic disorders. They may also be useful as novel diagnostics and therapeutics given their special features of non-immunogenicity and quick extraction. In this paper, we summarize the structure, content, and functions of exosomes and the potential diagnostic and therapeutic applications of exosome-associated microRNAs in the treatment of metabolic disorders.
The possible role of visceral fat in early pregnancy as a predictor of gestational diabetes mellitus by regulating adipose-derived exosomes miRNA-148 family: protocol for a nested case-control study in a cohort study.
Zhang Zhenhong,Xu Qian,Chen Yanping,Sui Lun,Jiang Lu,Shen Qianqian,Li Minyu,Li Guoju,Wang Qiuzhen
BMC pregnancy and childbirth
BACKGROUND:Gestational diabetes mellitus (GDM) has become alarming public health concern. It is associated with adverse pregnancy outcomes and increased risk of postpartum type 2 diabetes. Pre-pregnant body mass index (BMI), waist circumference and other anthropometric parameters have been proposed to predict GDM. However, visceral fat thickness can better reflect the distribution of body fat, and may more accurately predict the risk of GDM. Visceral fat thickness may lead to insulin resistance by regulating the adipose-derived exosomes miRNA-148 family, which affect the development of GDM. Evidence from prospective cohort studies on visceral fat thickness as a predictor of GDM and the possible mechanisms is still insufficient. METHODS:In this prospective cohort study, we will recruit 3000 women at first antenatal visit between 4 and 12 weeks of gestation. Baseline socio-demographic factors and visceral fat thickness will be assessed by questionnaire form and the ultrasonic measurement, respectively. At 20 weeks of gestation, 10 ml blood samples will be drawn and we will extract adipose-derived exosomes miRNA on the basis of nested case-control study. GDM will be screened at 24-28 weeks' gestation and the expression of miRNA-148 family between pregnant women with GDM and without GDM will be analyzed. Intermediary analysis will be used to investigate whether visceral fat thickness can predict GDM by regulating adipose-derived exosomes miRNA-148 family. DISCUSSION:We hypothesized that visceral fat thickness may predict GDM by regulating the miRNA-148 family of adipose-derived exosomes. The findings of the study will assist in further clarifying the pathophysiological mechanism of GDM, it will also provide technical support for effective screening of high-risk pregnant women with GDM.
Berberine alleviates type 2 diabetic symptoms by altering gut microbiota and reducing aromatic amino acids.
Yao Ye,Chen Han,Yan Lijing,Wang Wenbo,Wang Dongsheng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
OBJECTIVE:Berberine (BBR), which is extracted from traditional Chinese herb, is abundant in Coptis chinensis and Berberis vulgaris, with a treatment on type 2 diabetes mellitus (T2DM). However, its oral bioavailability is poor. Therefore, the ability of BBR to regulate gut microbiota and intestinal metabolites might exist. This study aimed to investigate changes in gut microbiota and intestinal metabolites, and to reveal the potential mechanism of BBR. METHODS:To observe the role of gut microbiota in the treatment of T2DM by BBR, antibiotics intervened gut microbiota was used in this study, and the therapeutic effects of BBR were evaluated. A 16S rRNA gene sequencing approach was utilized to analyze gut microbiota alterations, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identity differential intestinal metabolites. Finally, serum aromatic amino acids (AAAs) were absolutely quantified using LC/MS. RESULTS:Inhibition of the blood glucose levels, and improvements in glucose tolerance and serum lipid parameters were observed in the BBR treated group. Type 2 diabetic symptoms in rats in the BA group (treated with antibotics and BBR) were alleviated. However, the therapeutical effects are weaker in the BA group compared with the BBR group, indicating that BBR can be used to treat type 2 diabetic rats immediately, and modulation of gut microbiota is related to the mechanism of BBR in the treatment of T2DM. The community richness and diversity of the gut microbiota were significantly increased by BBR, and the relative abundance of Bacteroidetes was increased in the BBR group, which was accompanied by a decreased relative abundance of Proteobacteria and Verrucomicrobia at the phylum level. At the family level, a probiotic Lactobacillaceae was significantly upregulated not only in the BBR group but also in the BA group and was negatively associated with the risk of T2DM. Metabolomic analysis of colon contents identified 55 differential intestinal metabolites between the BBR group and the model group. AAAs, including tyrosine, tryptophan and phenylalanine, were obviously decreased in the BBR group not only in the colon contents but also in the serum. CONCLUSIONS:These results demonstrated that BBR could alleviate symptoms in type 2 diabetic rats by affecting gut microbiota composition and reducing the concentration of AAAs.
Berberine (BBR) Attenuated Palmitic Acid (PA)-Induced Lipotoxicity in Human HK-2 Cells by Promoting Peroxisome Proliferator-Activated Receptor α (PPAR-α).
Wu Yueyue,Chen Fangyuan,Huang Xinmei,Zhang Rui,Yu Zhiyan,Chen Zaoping,Liu Jun
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Berberine (BBR), a natural alkaloid isolated from Coptis chinensis, has frequently been reported as an antidiabetic reagent, partly due to its lipid-lowering activity. Evidence suggests that BBR ameliorates palmitate-induced lipid deposition and apoptosis in renal tubular epithelial cells (TECs), which tracks in tandem with the enhancement of peroxisome proliferator-activated receptor alpha (PPAR-alpha). The study aim was to investigate the roles of BBR in renal lipotoxicity in vitro, and investigate whether PPAR-alpha was the underlying mechanism. MATERIAL AND METHODS Human TECs (HK-2 cells) were injured with palmitic acid (PA), and then treated with BBR, BBR+PPAR-alpha inhibitor (GW6471), and PA+PPAR-alpha agonist (fenofibrate). Endoplasmic reticulum (ER) stress was assessed by measuring the expression of prospective evaluation of radial keratotomy (PERK), C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). Lipid metabolism was assessed by determining lipid anabolism-associated genes, including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL), as well as lipid catabolism-associated gene, including carnitine palmitoyl transferase 1 (CPT1). Inflammatory response of HK-2 cells was evaluated by measuring interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. Cell apoptosis and protein levels of cleaved-caspase-3 were evaluated. RESULTS PA downregulated PPAR-alpha and induced server lipotoxicity in HK-2 cells by ER stress, increasing lipid deposition, and elevating inflammatory response of HK-2 cells accompanied with inducting cell apoptosis and cleaved-caspase-3, which were obviously reversed by additional treatment of BBR or PPAR-alpha agonist. However, the protective effect of BBR in PA-induced lipotoxicity in HK-2 cells was significantly ameliorated by PPAR-alpha inhibitor. CONCLUSIONS BBR attenuated PA-induced lipotoxicity via the PPAR-alpha pathway.
[Research progress in the role and mechanism of polysaccharides in regulating glucose and lipid metabolism].
Ding M,Wang G,Yuan P,He S,Shao T,Liu C,Kong X
Nan fang yi ke da xue xue bao = Journal of Southern Medical University
Polysaccharides are a group of compounds composed of multiple monosaccharides of the same or different structures combined by glycosidic bonds, and are widely found in animals and plants and in the cell walls of microorganisms. Polysaccharides possess the advantages of high safety and low toxicity. Recent studies revealed that polysaccharides have a wide range of biological activities including immunoregulation, anti-tumor, antiviral, antioxidant activities, and blood glucose-and lipid- lowering effects. The effects of polysaccharides in improving insulin sensitivity and regulating glucose and lipid metabolism have drawn much attention from researchers. Many polysaccharides can reduce blood glucose and blood lipid by repairing pancreatic islet cells, improving insulin resistance, regulating intestinal flora, enhancing antioxidant capacity, and regulating the activities of key enzymes in glucose and lipid metabolism. This reviews examines the role and mechanism of polysaccharides in regulating glucose and lipid metabolism. The mechanisms of polysaccharide in regulating glucose metabolism include repairing islet cells and increasing insulin content, increasing insulin sensitivity and improving insulin resistance, regulating the activity of key enzymes in glucose metabolism, increasing synthesis of liver glycogen, and regulating intestinal flora. Polysaccharides can also regulate glucose metabolism by improving immune regulation and antagonizing glucagon. Polysaccharide also regulate lipid metabolism by regulating lipid absorption, expression of the related genes such as PPAR-α, enzyme activities in lipid metabolism, improving antioxidant capacity, and modulating intestinal flora and signaling pathways.
Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism.
Soto Marion,Herzog Clémence,Pacheco Julian A,Fujisaka Shiho,Bullock Kevin,Clish Clary B,Kahn C Ronald
Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.
Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism.
Krishnaiah Saikumari Y,Wu Gang,Altman Brian J,Growe Jacqueline,Rhoades Seth D,Coldren Faith,Venkataraman Anand,Olarerin-George Anthony O,Francey Lauren J,Mukherjee Sarmistha,Girish Saiveda,Selby Christopher P,Cal Sibel,Er Ubeydullah,Sianati Bahareh,Sengupta Arjun,Anafi Ron C,Kavakli I Halil,Sancar Aziz,Baur Joseph A,Dang Chi V,Hogenesch John B,Weljie Aalim M
The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, ∼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.
Microbial metabolites regulate host lipid metabolism through NR5A-Hedgehog signalling.
Lin Chih-Chun Janet,Wang Meng C
Nature cell biology
Microorganisms and their hosts share the same environment, and microbial metabolic molecules (metabolites) exert crucial effects on host physiology. Environmental factors not only shape the composition of the host's resident microorganisms, but also modulate their metabolism. However, the exact molecular relationship among the environment, microbial metabolites and host metabolism remains largely unknown. Here, we discovered that environmental methionine tunes bacterial methyl metabolism to regulate host mitochondrial dynamics and lipid metabolism in Caenorhabditis elegans through an endocrine crosstalk involving NR5A nuclear receptor and Hedgehog signalling. We discovered that methionine deficiency in bacterial medium decreases the production of bacterial metabolites that are essential for phosphatidylcholine synthesis in C. elegans. Reductions of diundecanoyl and dilauroyl phosphatidylcholines attenuate NHR-25, a NR5A nuclear receptor, and release its transcriptional suppression of GRL-21, a Hedgehog-like protein. The induction of GRL-21 consequently inhibits the PTR-24 Patched receptor cell non-autonomously, resulting in mitochondrial fragmentation and lipid accumulation. Together, our work reveals an environment-microorganism-host metabolic axis regulating host mitochondrial dynamics and lipid metabolism, and discovers NR5A-Hedgehog intercellular signalling that controls these metabolic responses with critical consequences for host health and survival.
Host-Microbe-Drug-Nutrient Screen Identifies Bacterial Effectors of Metformin Therapy.
Pryor Rosina,Norvaisas Povilas,Marinos Georgios,Best Lena,Thingholm Louise B,Quintaneiro Leonor M,De Haes Wouter,Esser Daniela,Waschina Silvio,Lujan Celia,Smith Reuben L,Scott Timothy A,Martinez-Martinez Daniel,Woodward Orla,Bryson Kevin,Laudes Matthias,Lieb Wolfgang,Houtkooper Riekelt H,Franke Andre,Temmerman Liesbet,Bjedov Ivana,Cochemé Helena M,Kaleta Christoph,Cabreiro Filipe
Metformin is the first-line therapy for treating type 2 diabetes and a promising anti-aging drug. We set out to address the fundamental question of how gut microbes and nutrition, key regulators of host physiology, affect the effects of metformin. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we developed a high-throughput four-way screen to define the underlying host-microbe-drug-nutrient interactions. We show that microbes integrate cues from metformin and the diet through the phosphotransferase signaling pathway that converges on the transcriptional regulator Crp. A detailed experimental characterization of metformin effects downstream of Crp in combination with metabolic modeling of the microbiota in metformin-treated type 2 diabetic patients predicts the production of microbial agmatine, a regulator of metformin effects on host lipid metabolism and lifespan. Our high-throughput screening platform paves the way for identifying exploitable drug-nutrient-microbiome interactions to improve host health and longevity through targeted microbiome therapies. VIDEO ABSTRACT.
Physiological and pathophysiological roles of NAMPT and NAD metabolism.
Garten Antje,Schuster Susanne,Penke Melanie,Gorski Theresa,de Giorgis Tommaso,Kiess Wieland
Nature reviews. Endocrinology
Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.
An obligatory role for neurotensin in high-fat-diet-induced obesity.
Li Jing,Song Jun,Zaytseva Yekaterina Y,Liu Yajuan,Rychahou Piotr,Jiang Kai,Starr Marlene E,Kim Ji Tae,Harris Jennifer W,Yiannikouris Frederique B,Katz Wendy S,Nilsson Peter M,Orho-Melander Marju,Chen Jing,Zhu Haining,Fahrenholz Timothy,Higashi Richard M,Gao Tianyan,Morris Andrew J,Cassis Lisa A,Fan Teresa W-M,Weiss Heidi L,Dobner Paul R,Melander Olle,Jia Jianhang,Evers B Mark
Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.
Sphingolipids and phospholipids in insulin resistance and related metabolic disorders.
Meikle Peter J,Summers Scott A
Nature reviews. Endocrinology
Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.
Toward Connecting Metabolism to the Exocytotic Site.
Ferdaoussi Mourad,MacDonald Patrick E
Trends in cell biology
Within cells the regulated exocytosis of secretory granules controls multiple physiological functions, including endocrine hormone secretion. Release of the glucose-regulating hormone insulin from pancreatic islet β cells is critical for whole-body metabolic homeostasis. Impaired insulin secretion appears early in the progression to type 2 diabetes (T2D). Key mechanisms that control the β-cell exocytotic response, mediating the long-known but little understood metabolic amplification of insulin secretion, are becoming clearer. Recent insights indicate a convergence of metabolism-driven signals, such as lipid-derived messengers and redox-dependent deSUMOylation, at the plasma membrane to augment Ca-dependent insulin exocytosis. These pathways have important implications for the metabolic control of hormone secretion, for the functional compensation that occurs in obesity, and for impaired insulin secretion in diabetes.
Fatty acid synthesis configures the plasma membrane for inflammation in diabetes.
Wei Xiaochao,Song Haowei,Yin Li,Rizzo Michael G,Sidhu Rohini,Covey Douglas F,Ory Daniel S,Semenkovich Clay F
Dietary fat promotes pathological insulin resistance through chronic inflammation. The inactivation of inflammatory proteins produced by macrophages improves diet-induced diabetes, but how nutrient-dense diets induce diabetes is unknown. Membrane lipids affect the innate immune response, which requires domains that influence high-fat-diet-induced chronic inflammation and alter cell function based on phospholipid composition. Endogenous fatty acid synthesis, mediated by fatty acid synthase (FAS), affects membrane composition. Here we show that macrophage FAS is indispensable for diet-induced inflammation. Deleting Fasn in macrophages prevents diet-induced insulin resistance, recruitment of macrophages to adipose tissue and chronic inflammation in mice. We found that FAS deficiency alters membrane order and composition, impairing the retention of plasma membrane cholesterol and disrupting Rho GTPase trafficking-a process required for cell adhesion, migration and activation. Expression of a constitutively active Rho GTPase, however, restored inflammatory signalling. Exogenous palmitate was partitioned to different pools from endogenous lipids and did not rescue inflammatory signalling. However, exogenous cholesterol, as well as other planar sterols, did rescue signalling, with cholesterol restoring FAS-induced perturbations in membrane order. Our results show that the production of endogenous fat in macrophages is necessary for the development of exogenous-fat-induced insulin resistance through the creation of a receptive environment at the plasma membrane for the assembly of cholesterol-dependent signalling networks.
A global perspective on FOXO1 in lipid metabolism and lipid-related diseases.
Li Yue,Ma Zhiqiang,Jiang Shuai,Hu Wei,Li Tian,Di Shouyin,Wang Dongjin,Yang Yang
Progress in lipid research
Lipid metabolism is a complex physiological process that is involved in nutrient adjustment, hormone regulation, and homeostasis. An unhealthy lifestyle and chronic nutrient overload can cause lipid metabolism disorders, which may lead to serious lipid-related diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus (T2DM). Therefore, tools for preventing dysfunctional lipid metabolism are urgently needed. The transcription factor forkhead box protein O1 (FOXO1) is involved in lipid metabolism and plays a critical role in the development of lipid-related diseases. In this review, we provide a global perspective on the role of FOXO1 in lipid metabolism and lipid-related diseases. The information included here may be useful for the design of future studies and advancing investigations of FOXO1 as a therapeutic target.
D-mannose induces regulatory T cells and suppresses immunopathology.
Zhang Dunfang,Chia Cheryl,Jiao Xue,Jin Wenwen,Kasagi Shimpei,Wu Ruiqing,Konkel Joanne E,Nakatsukasa Hiroko,Zanvit Peter,Goldberg Nathan,Chen Qianming,Sun Lingyun,Chen Zi-Jiang,Chen WanJun
D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3 regulatory T cells (T cells) in mice. In vitro, D-mannose stimulated T cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αβ and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.
Liver X receptors in lipid signalling and membrane homeostasis.
Wang Bo,Tontonoz Peter
Nature reviews. Endocrinology
Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.
Genetic deficiency of indoleamine 2,3-dioxygenase promotes gut microbiota-mediated metabolic health.
Laurans Ludivine,Venteclef Nicolas,Haddad Yacine,Chajadine Mouna,Alzaid Fawaz,Metghalchi Sarvenaz,Sovran Bruno,Denis Raphael G P,Dairou Julien,Cardellini Marina,Moreno-Navarrete Jose-Maria,Straub Marjolene,Jegou Sarah,McQuitty Claire,Viel Thomas,Esposito Bruno,Tavitian Bertrand,Callebert Jacques,Luquet Serge H,Federici Massimo,Fernandez-Real José Manuel,Burcelin Remy,Launay Jean-Marie,Tedgui Alain,Mallat Ziad,Sokol Harry,Taleb Soraya
The association between altered gut microbiota, intestinal permeability, inflammation and cardiometabolic diseases is becoming increasingly clear but remains poorly understood. Indoleamine 2,3-dioxygenase is an enzyme induced in many types of immune cells, including macrophages in response to inflammatory stimuli, and catalyzes the degradation of tryptophan along the kynurenine pathway. Indoleamine 2,3-dioxygenase activity is better known for its suppression of effector T cell immunity and its activation of regulatory T cells. However, high indoleamine 2,3-dioxygenase activity predicts worse cardiovascular outcome and may promote atherosclerosis and vascular inflammation, suggesting a more complex role in chronic inflammatory settings. Indoleamine 2,3-dioxygenase activity is also increased in obesity, yet its role in metabolic disease is still unexplored. Here, we show that obesity is associated with an increase of intestinal indoleamine 2,3-dioxygenase activity, which shifts tryptophan metabolism from indole derivative and interleukin-22 production toward kynurenine production. Indoleamine 2,3-dioxygenase deletion or inhibition improves insulin sensitivity, preserves the gut mucosal barrier, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. These beneficial effects are due to rewiring of tryptophan metabolism toward a microbiota-dependent production of interleukin-22 and are abrogated after treatment with a neutralizing anti-interleukin-22 antibody. In summary, we identify an unexpected function of indoleamine 2,3-dioxygenase in the fine tuning of intestinal tryptophan metabolism with major consequences on microbiota-dependent control of metabolic disease, which suggests indoleamine 2,3-dioxygenase as a potential therapeutic target.
A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress.
Anderson Ethan J,Vistoli Giulio,Katunga Lalage A,Funai Katsuhiko,Regazzoni Luca,Monroe T Blake,Gilardoni Ettore,Cannizzaro Luca,Colzani Mara,De Maddis Danilo,Rossoni Giuseppe,Canevotti Renato,Gagliardi Stefania,Carini Marina,Aldini Giancarlo
The Journal of clinical investigation
Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.
Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes.
Goedeke Leigh,Perry Rachel J,Shulman Gerald I
Annual review of pharmacology and toxicology
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
Molecular pathways linking adipose innervation to insulin action in obesity and diabetes mellitus.
Guilherme Adilson,Henriques Felipe,Bedard Alexander H,Czech Michael P
Nature reviews. Endocrinology
Adipose tissue comprises adipocytes and many other cell types that engage in dynamic crosstalk in a highly innervated and vascularized tissue matrix. Although adipose tissue has been studied for decades, it has been appreciated only in the past 5 years that extensive arborization of nerve fibres has a dominant role in regulating the function of adipose tissue. This Review summarizes the latest literature, which suggests that adipocytes signal to local sensory nerve fibres in response to perturbations in lipolysis and lipogenesis. Such adipocyte signalling to the central nervous system causes sympathetic output to distant adipose depots and potentially other metabolic tissues to regulate systemic glucose homeostasis. Paracrine factors identified in the past few years that mediate such adipocyte-neuron crosstalk are also reviewed. Similarly, immune cells and endothelial cells within adipose tissue communicate with local nerve fibres to modulate neurotransmitter tone, blood flow, adipocyte differentiation and energy expenditure, including adipose browning to produce heat. This understudied field of neurometabolism related to adipose tissue biology has great potential to reveal new mechanistic insights and potential therapeutic strategies for obesity and type 2 diabetes mellitus.
The Liver-α-Cell Axis and Type 2 Diabetes.
Wewer Albrechtsen Nicolai J,Pedersen Jens,Galsgaard Katrine D,Winther-Sørensen Marie,Suppli Malte P,Janah Lina,Gromada Jesper,Vilstrup Hendrik,Knop Filip K,Holst Jens J
Both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) strongly associate with increasing body mass index, and together these metabolic diseases affect millions of individuals. In patients with T2D, increased secretion of glucagon (hyperglucagonemia) contributes to diabetic hyperglycemia as proven by the significant lowering of fasting plasma glucose levels following glucagon receptor antagonist administration. Emerging data now indicate that the elevated plasma concentrations of glucagon may also be associated with hepatic steatosis and not necessarily with the presence or absence of T2D. Thus, fatty liver disease, most often secondary to overeating, may result in impaired amino acid turnover, leading to increased plasma concentrations of certain glucagonotropic amino acids (e.g., alanine). This, in turn, causes increased glucagon secretion that may help to restore amino acid turnover and ureagenesis, but it may eventually also lead to increased hepatic glucose production, a hallmark of T2D. Early experimental findings support the hypothesis that hepatic steatosis impairs glucagon's actions on amino acid turnover and ureagenesis. Hepatic steatosis also impairs hepatic insulin sensitivity and clearance that, together with hyperglycemia and hyperaminoacidemia, lead to peripheral hyperinsulinemia; systemic hyperinsulinemia may itself contribute to worsen peripheral insulin resistance. Additionally, obesity is accompanied by an impaired incretin effect, causing meal-related glucose intolerance. Lipid-induced impairment of hepatic sensitivity, not only to insulin but potentially also to glucagon, resulting in both hyperinsulinemia and hyperglucagonemia, may therefore contribute to the development of T2D at least in a subset of individuals with NAFLD.
Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance.
Turpin Sarah M,Nicholls Hayley T,Willmes Diana M,Mourier Arnaud,Brodesser Susanne,Wunderlich Claudia M,Mauer Jan,Xu Elaine,Hammerschmidt Philipp,Brönneke Hella S,Trifunovic Aleksandra,LoSasso Giuseppe,Wunderlich F Thomas,Kornfeld Jan-Wilhelm,Blüher Matthias,Krönke Martin,Brüning Jens C
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6(Δ/Δ)) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6(Δ/Δ) mice, but also in brown adipose tissue- (CerS6(ΔBAT)) and liver-specific (CerS6(ΔLIVER)) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.
A new biology of diabetes revealed by leptin.
Unger Roger H,Roth Michael G
A variety of leptin actions require a re-examination of classic concepts of metabolic diseases. Here we present evidence for two physiologic pathways: a pathway that protects nonadipose tissues from overaccumulation of potentially toxic lipids and unrecognized paracrine interactions between α and β cells revealed by leptin's ability to suppress diabetic hyperglucagonemia. These observations strongly point to new therapeutic possibilities for both type 1 and type 2 diabetes.
Targeting ceramide metabolism in obesity.
Aburasayn Hanin,Al Batran Rami,Ussher John R
American journal of physiology. Endocrinology and metabolism
Obesity is a major health concern that increases the risk for insulin resistance, type 2 diabetes (T2D), and cardiovascular disease. Thus, an enormous research effort has been invested into understanding how obesity-associated dyslipidemia and obesity-induced alterations in lipid metabolism increase the risk for these diseases. Accordingly, it has been proposed that the accumulation of lipid metabolites in organs such as the liver, skeletal muscle, and heart is critical to these obesity-induced pathologies. Ceramide is one such lipid metabolite that accumulates in tissues in response to obesity, and both pharmacological and genetic strategies that reduce tissue ceramide levels yield salutary actions on overall metabolic health. We will review herein why ceramide accumulates in tissues during obesity and how an increase in intracellular ceramide impacts cellular signaling and function as well as potential mechanisms by which reducing intracellular ceramide levels improves insulin resistance, T2D, atherosclerosis, and heart failure. Because a reduction in skeletal muscle ceramide levels is frequently associated with improvements in insulin sensitivity in humans, the beneficial findings reported for reducing ceramides in preclinical studies may have clinical application in humans. Therefore, modulating ceramide metabolism may be a novel, exciting target for preventing and/or treating obesity-related diseases.
The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach.
Raichur Suryaprakash,Brunner Bodo,Bielohuby Maximilian,Hansen Gitte,Pfenninger Anja,Wang Bing,Bruning Jens C,Larsen Philip Just,Tennagels Norbert
OBJECTIVE:Ectopic fat deposition is associated with increased tissue production of ceramides. Recent genetic mouse studies suggest that specific sphingolipid C16:0 ceramide produced by ceramide synthase 6 (CerS6) plays an important role in the development of insulin resistance. However, the therapeutic potential of CerS6 inhibition not been demonstrated. Therefore, we pharmacologically investigated the selective ablation of CerS6 using antisense oligonucleotides (ASO) in obese insulin resistance animal models. METHODS:We utilized ASO as therapeutic modality, CerS6 ASO molecules designed and synthesized were initially screened for in-vitro knock-down (KD) potency and cytotoxicity. ASOs with >85% inhibition of CerS6 mRNA were selected for further investigations. Most promising ASOs verified for in-vivo KD efficacy in healthy mice. CerS6 ASO (AAGATGAGCCGCACC) was found most active with hepatic reduction of CerS6 mRNA expression. Prior to longitudinal metabolic studies, we performed a dose titration target engagement analysis with CerS6 ASO in healthy mice to select the optimal dose. Next, we utilized leptin deficiency ob/ob and high fat diet (HFD) induced obese mouse models for pharmacological efficacy study. RESULTS:CerS6 expression were significantly elevated in the liver and brown adipose, this was correlated with significantly elevated C16:0 ceramide concentrations in plasma and liver. Treatment with CerS6 ASO selectively reduced CerS6 expression by ∼90% predominantly in the liver and this CerS6 KD resulted in a significant reduction of C16:0 ceramide by about 50% in both liver and plasma. CerS6 KD resulted in lower body weight gain and accompanied by a significant reduction in whole body fat and fed/fasted blood glucose levels (1% reduction in HbA1c). Moreover, ASO-mediated CerS6 KD significantly improved oral glucose tolerance (during oGTT) and mice displayed improved insulin sensitivity. Thus, CerS6 appear to play an important role in the development of obesity and insulin resistance. CONCLUSIONS:Our investigations identified specific and selective therapeutic valid ASO for CerS6 ablation in in-vivo. CerS6 should specifically be targeted for the reduction of C16:0 ceramides, that results in amelioration of insulin resistance, hyperglycemia and obesity. CerS6 mediated C16:0 ceramide reduction could be a potentially attractive target for the treatment of insulin resistance, obesity and type 2 diabetes.
Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism.
Chaurasia Bhagirath,Kaddai Vincent Andre,Lancaster Graeme Iain,Henstridge Darren C,Sriram Sandhya,Galam Dwight Lark Anolin,Gopalan Venkatesh,Prakash K N Bhanu,Velan S Sendhil,Bulchand Sarada,Tsong Teh Jing,Wang Mei,Siddique Monowarul Mobin,Yuguang Guan,Sigmundsson Kristmundur,Mellet Natalie A,Weir Jacquelyn M,Meikle Peter J,Bin M Yassin M Shabeer,Shabbir Asim,Shayman James A,Hirabayashi Yoshio,Shiow Sue-Anne Toh Ee,Sugii Shigeki,Summers Scott A
Adipocytes package incoming fatty acids into triglycerides and other glycerolipids, with only a fraction spilling into a parallel biosynthetic pathway that produces sphingolipids. Herein, we demonstrate that subcutaneous adipose tissue of type 2 diabetics contains considerably more sphingolipids than non-diabetic, BMI-matched counterparts. Whole-body and adipose tissue-specific inhibition/deletion of serine palmitoyltransferase (Sptlc), the first enzyme in the sphingolipid biosynthesis cascade, in mice markedly altered adipose morphology and metabolism, particularly in subcutaneous adipose tissue. The reduction in adipose sphingolipids increased brown and beige/brite adipocyte numbers, mitochondrial activity, and insulin sensitivity. The manipulation also increased numbers of anti-inflammatory M2 macrophages in the adipose bed and induced secretion of insulin-sensitizing adipokines. By comparison, deletion of serine palmitoyltransferase from macrophages had no discernible effects on metabolic homeostasis or adipose function. These data indicate that newly synthesized adipocyte sphingolipids are nutrient signals that drive changes in the adipose phenotype to influence whole-body energy expenditure and nutrient metabolism.
Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes.
Bellini Lara,Campana Mélanie,Mahfouz Rana,Carlier Aurélie,Véret Julien,Magnan Christophe,Hajduch Eric,Le Stunff Hervé
Expert opinion on therapeutic targets
INTRODUCTION:Obesity is a major factor that is linked to the development of type 2 diabetes (T2D). Excess circulating fatty acids (FAs), which characterize obesity, induce insulin resistance, steatosis, β cells dysfunction and apoptosis. These deleterious effects have been defined as lipotoxicity. AREAS COVERED:FAs are metabolized to different lipid species, including ceramides which play a crucial role in lipotoxicity. The action of ceramides on tissues, such as muscle, liver, adipose tissue and pancreatic β cells, during the development of T2D will also be reviewed. In addition, the potential antagonist action of other sphingolipids, namely sphingoid base phosphates, on lipotoxicity in skeletal muscle and β cells will be addressed. EXPERT OPINION:Ceramide is a critical mediator to the development of T2D linked to obesity. Targeting proteins involved in ceramide's deleterious action has not been possible due to their involvement in many other intracellular signaling pathways. A possible means of counteracting ceramide action would be to prevent the accumulation of the specific ceramide species involved in both insulin resistance and β-cell apoptosis/dysfunction. Another possibility would be to adjust the dynamic balance between ceramide and sphingoid base phosphate, both known to display opposing properties on the development of T2D-linked obesity.
Role of sphingolipids in senescence: implication in aging and age-related diseases.
Trayssac Magali,Hannun Yusuf A,Obeid Lina M
The Journal of clinical investigation
Aging is defined as the progressive deterioration of physiological function with age. Incidence of many pathologies increases with age, including neurological and cardiovascular diseases and cancer. Aging tissues become less adaptable and renewable, and cells undergo senescence, a process by which they "irreversibly" stop dividing. Senescence has been shown to serve as a tumor suppression mechanism with clear desirable effects. However, senescence also has deleterious consequences, especially for cardiovascular, metabolic, and immune systems. Sphingolipids are a major class of lipids that regulate cell biology, owing to their structural and bioactive properties and diversity. Their involvement in the regulation of aging and senescence has been demonstrated and studied in multiple organisms and cell types, especially that of ceramide and sphingosine-1-phosphate; ceramide induces cellular senescence and sphingosine-1-phosphate delays it. These discoveries could be very useful in the future to understand aging mechanisms and improve therapeutic interventions.
Scutellariae radix and coptidis rhizoma ameliorate glycolipid metabolism of type 2 diabetic rats by modulating gut microbiota and its metabolites.
Xiao Suwei,Liu Chen,Chen Mengjun,Zou Junfeng,Zhang Zhimiao,Cui Xiang,Jiang Shu,Shang Erxin,Qian Dawei,Duan Jinao
Applied microbiology and biotechnology
Scutellariae radix (Scutellaria baicalensis Georgi, SR) and coptidis rhizoma (Coptis chinensis Franch, CR) are both widely used traditional Chinese medicines and have been used together to treat T2DM with synergistic effects in the clinical practices for thousands of years, but their combination mechanism is not clear. Accumulating evidences have implicated gut microbiota as important targets for the therapy of T2DM. Thus, this study aimed to unravel the cooperation mechanism of SR and CR on the amelioration of T2DM based on the systematic analysis of metagenome and metabolome of gut microbiota. Bacterial communities were analyzed based on high-throughput 16S rRNA gene sequencing. Furthermore, ultra high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS) was used to analyze variations of microbial metabolites in feces and the contents of short chain fatty acids (SCFAs) in the cecum were determined by a gaschromatography-flame ionization detector (GC-FID). 16S rRNA gene sequencing results revealed that T2DM rats treated with SR, CR, and the combination of SR and CR (SC) exhibited changes in the composition of the gut microbiota. The SCFAs-producing bacteria such as Bacteroidales S24-7 group_norank, [Eubacterium] nodatum group, Parasutterella, Prevotellaceae UCG-001, Ruminiclostridium, and Ruminiclostridium 9 in T2DM rats were notably enriched after treatment with SR, CR, and their combination. In contrast, secondary bile acid-producing bacteria such as Escherichia-Shigella strongly decreased in numbers. The perturbance of metabolic profiling in T2DM rats was obviously improved after treatment, exhibiting a lower level of secondary bile acids and a numerical increase of microbially derived SCFAs. Moreover, the correlation analysis illustrated a close relationship among gut microbiota, its metabolites, and T2DM-related indexes. The findings indicated that the crosstalk between microbiota-derived metabolites and the host played an important role in the progress of T2DM and might provide a novel insight regarding gut microbiota and its metabolites as potential new targets of traditional Chinese medicines. Furthermore, this work also suggested that the integration of various omics methods and bioinformatics made a useful template for drug mechanism research.
New insights on association between circadian rhythm and lipid metabolism in spontaneously hypertensive rats.
Hou Qingqing,Zhang Shiming,Li Yuan,Wang Huanjun,Zhang Dan,Qi Dongmei,Li Yunlun,Jiang Haiqiang
AIMS:The aim of this study is to provide new insights on the association of lipid metabolites, circadian genes and lipid metabolism associated genes in spontaneously hypertensive rats. MATERIALS AND METHODS:An untargeted lipidomics using ultrahigh performance liquid chromatography-mass spectrometry metabolomics was used to identify the differentially expressed lipid metabolites over 24 h in Spontaneously hypertensive rats (SHR) with reference to Wistar-Kyoto rats (WKY). The expression of circadian clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2) and lipid metabolism related genes (Rev-erbα, Pparα and Sirt1) was analysed RT-qPCR. KEY FINDINGS:Ten lipid metabolites with significant differences in their levels in SHR compared to WKY were identified. The levels of MG (25:0), PA (36:3) and PE (38:2) were lower and the levels of LysoPCs (20:0 and 20:3) and TGs (54:5, 59:12, 28:0, 60:10 and 60:13) were found to be higher in SHR. SHR showed obvious disorders in the expression of circadian genes and lipid metabolism associated genes. A strong association between the levels of lipid metabolites and circadian genes and lipid metabolism associated genes was found. SIGNIFICANCE:Rhythm genes may further affect the 24-hour lipid metabolism level of spontaneously hypertensive rats by mediating lipid metabolism associated genes. This research provides new insights on the association of lipid metabolites, circadian genes and lipid metabolism associated genes in SHR.
Weight Gain and Impaired Glucose Metabolism in Women Are Predicted by Inefficient Subcutaneous Fat Cell Lipolysis.
Arner Peter,Andersson Daniel P,Bäckdahl Jesper,Dahlman Ingrid,Rydén Mikael
Adipocyte mobilization of fatty acids (lipolysis) is instrumental for energy expenditure. Lipolysis displays both spontaneous (basal) and hormone-stimulated activity. It is unknown if lipolysis is important for future body weight gain and associated disturbed glucose metabolism, and this was presently investigated in subcutaneous adipocytes from two female cohorts before and after ≥10-year follow-up. High basal and low stimulated lipolysis at baseline predicted future weight gain (odds ratios ≥4.6) as well as development of insulin resistance and impaired fasting glucose/type 2 diabetes (odds ratios ≥3.2). At baseline, weight gainers displayed lower adipose expression of several established lipolysis-regulating genes. Thus, inefficient lipolysis (high basal/low stimulated) involving altered gene expression is linked to future weight gain and impaired glucose metabolism and may constitute a treatment target. Finally, low stimulated lipolysis could be accurately estimated in vivo by simple clinical/biochemical measures and may be used to identify risk individuals for intensified preventive measures.
Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives.
Arab Juan P,Karpen Saul J,Dawson Paul A,Arrese Marco,Trauner Michael
Hepatology (Baltimore, Md.)
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2017;65:350-362).
Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Pathak Preeti,Xie Cen,Nichols Robert G,Ferrell Jessica M,Boehme Shannon,Krausz Kristopher W,Patterson Andrew D,Gonzalez Frank J,Chiang John Y L
Hepatology (Baltimore, Md.)
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the FEX-induced metabolic phenotypes and inhibited taurolithocholic acid synthesis, adipose tissue browning, and liver bile acid synthesis gene expression but further increased intestinal FXR target gene expression. FEX treatment effectively improved lipid profiles, increased GLP-1 secretion, improved glucose and insulin tolerance, and promoted adipose tissue browning, while antibiotic treatment reversed the beneficial metabolic effects of FEX in obese and diabetic mice. CONCLUSION:This study uncovered a mechanism in which activation of intestinal FXR shaped the gut microbiota to activate TGR5/GLP-1 signaling to improve hepatic glucose and insulin sensitivity and increase adipose tissue browning; the gut microbiota plays a critical role in bile acid metabolism and signaling to regulate metabolic homeostasis in health and disease. (Hepatology 2018).
Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome.
Kita Shunbun,Maeda Norikazu,Shimomura Iichiro
The Journal of clinical investigation
Adipose tissue plays important roles in regulating whole-body energy metabolism through its storage function in white adipocytes and its dissipating function in brown and beige adipocytes. Adipose tissue also produces a variety of secreted factors called adipocytokines, including leptin and adiponectin. Furthermore, recent studies have suggested the important roles of extracellular vesicles of endosomal origin termed exosomes, which are secreted from adipocytes and other cells in adipose tissue and influence whole-body glucose and lipid metabolism. Adiponectin is known to be a pleiotropic organ-protective protein that is exclusively produced by adipocytes and decreased in obesity. Adiponectin accumulates in tissues such as heart, muscle, and vascular endothelium through binding with T-cadherin, a glycosylphosphatidylinositol-anchored (GPI-anchored) cadherin. Recently, adiponectin was found to enhance exosome biogenesis and secretion, leading to a decrease in cellular ceramides, excess of which is known to cause insulin resistance and cardiovascular disease phenotypes. These findings support the hypothesis that adipose tissue metabolism systemically regulates exosome production and whole-body metabolism through exosomes. This review focuses on intra-adipose and interorgan communication by exosomes, adiponectin-stimulated exosome production, and their dysregulation in metabolic diseases.
Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease.
Chávez-Talavera Oscar,Tailleux Anne,Lefebvre Philippe,Staels Bart
Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications.
Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs.
Ahmad Tiara R,Haeusler Rebecca A
Nature reviews. Endocrinology
Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.
Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes.
Fernández-Real José Manuel,McClain Donald,Manco Melania
OBJECTIVE:The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS:The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS:The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS:Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted.
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
Softic Samir,Gupta Manoj K,Wang Guo-Xiao,Fujisaka Shiho,O'Neill Brian T,Rao Tata Nageswara,Willoughby Jennifer,Harbison Carole,Fitzgerald Kevin,Ilkayeva Olga,Newgard Christopher B,Cohen David E,Kahn C Ronald
The Journal of clinical investigation
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.
Metabolites as regulators of insulin sensitivity and metabolism.
Yang Qin,Vijayakumar Archana,Kahn Barbara B
Nature reviews. Molecular cell biology
The cause of insulin resistance in obesity and type 2 diabetes mellitus (T2DM) is not limited to impaired insulin signalling but also involves the complex interplay of multiple metabolic pathways. The analysis of large data sets generated by metabolomics and lipidomics has shed new light on the roles of metabolites such as lipids, amino acids and bile acids in modulating insulin sensitivity. Metabolites can regulate insulin sensitivity directly by modulating components of the insulin signalling pathway, such as insulin receptor substrates (IRSs) and AKT, and indirectly by altering the flux of substrates through multiple metabolic pathways, including lipogenesis, lipid oxidation, protein synthesis and degradation and hepatic gluconeogenesis. Moreover, the post-translational modification of proteins by metabolites and lipids, including acetylation and palmitoylation, can alter protein function. Furthermore, the role of the microbiota in regulating substrate metabolism and insulin sensitivity is unfolding. In this Review, we discuss the emerging roles of metabolites in the pathogenesis of insulin resistance and T2DM. A comprehensive understanding of the metabolic adaptations involved in insulin resistance may enable the identification of novel targets for improving insulin sensitivity and preventing, and treating, T2DM.
Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice.
Kim Kang Ho,Choi Sungwoo,Zhou Ying,Kim Eun Young,Lee Jae Man,Saha Pradip K,Anakk Sayeepriyadarshini,Moore David D
Hepatology (Baltimore, Md.)
The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver-specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy-machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage. CONCLUSION:Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole-body energy homeostasis. (Hepatology 2017;66:498-509).
12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.
Leiria Luiz Osório,Wang Chih-Hao,Lynes Matthew D,Yang Kunyan,Shamsi Farnaz,Sato Mari,Sugimoto Satoru,Chen Emily Y,Bussberg Valerie,Narain Niven R,Sansbury Brian E,Darcy Justin,Huang Tian Lian,Kodani Sean D,Sakaguchi Masaji,Rocha Andréa L,Schulz Tim J,Bartelt Alexander,Hotamisligil Gökhan S,Hirshman Michael F,van Leyen Klaus,Goodyear Laurie J,Blüher Matthias,Cypess Aaron M,Kiebish Michael A,Spite Matthew,Tseng Yu-Hua
Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.
Stress-activated in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption.
Calo Nicolas,Ramadori Pierluigi,Sobolewski Cyril,Romero Yannick,Maeder Christine,Fournier Margot,Rantakari Pia,Zhang Fu-Ping,Poutanen Matti,Dufour Jean-François,Humar Bostjan,Nef Serge,Foti Michelangelo
OBJECTIVE: is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of in early stages of metabolic liver disorders associated with diet-induced obesity (DIO). DESIGN:Constitutive knockout (miR21KO) and liver-specific knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum and explanted liver tissue were analysed. RESULTS:Under normal breeding conditions and standard diet, deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lacking . Deletion of specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic in metabolic disorders associated with DIO. Further molecular analyses demonstrated that deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, lipogenesis, gluconeogenesis and glucose output. CONCLUSIONS:Hepatic deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points out * as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.
Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis.
McGlashon Jacob M,Gorecki Michelle C,Kozlowski Amanda E,Thirnbeck Caitlin K,Markan Kathleen R,Leslie Kirstie L,Kotas Maya E,Potthoff Matthew J,Richerson George B,Gillum Matthew P
Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes.
Fas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function.
Item Flurin,Wueest Stephan,Lemos Vera,Stein Sokrates,Lucchini Fabrizio C,Denzler Rémy,Fisser Muriel C,Challa Tenagne D,Pirinen Eija,Kim Youngsoo,Hemmi Silvio,Gulbins Erich,Gross Atan,O'Reilly Lorraine A,Stoffel Markus,Auwerx Johan,Konrad Daniel
Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance. In line, hepatocyte-specific ablation of Fas improves mitochondrial function and ameliorates high-fat-diet-induced hepatic steatosis, glucose tolerance, and insulin resistance. Mechanistically, Fas impairs fatty acid oxidation via the BH3 interacting-domain death agonist (BID). Mice with genetic or pharmacological inhibition of BID are protected from Fas-mediated impairment of mitochondrial oxidation and hepatic steatosis. We suggest Fas as a potential novel therapeutic target to treat obesity-associated fatty liver and insulin resistance.Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.
The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.
White Phillip J,McGarrah Robert W,Grimsrud Paul A,Tso Shih-Chia,Yang Wen-Hsuan,Haldeman Jonathan M,Grenier-Larouche Thomas,An Jie,Lapworth Amanda L,Astapova Inna,Hannou Sarah A,George Tabitha,Arlotto Michelle,Olson Lyra B,Lai Michelle,Zhang Guo-Fang,Ilkayeva Olga,Herman Mark A,Wynn R Max,Chuang David T,Newgard Christopher B
Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-β transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.
Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans.
Chondronikola Maria,Volpi Elena,Børsheim Elisabet,Porter Craig,Saraf Manish K,Annamalai Palam,Yfanti Christina,Chao Tony,Wong Daniel,Shinoda Kosaku,Labbė Sebastien M,Hurren Nicholas M,Cesani Fernardo,Kajimura Shingo,Sidossis Labros S
Recent studies suggest that brown adipose tissue (BAT) plays a role in energy and glucose metabolism in humans. However, the physiological significance of human BAT in lipid metabolism remains unknown. We studied 16 overweight/obese men during prolonged, non-shivering cold and thermoneutral conditions using stable isotopic tracer methodologies in conjunction with hyperinsulinemic-euglycemic clamps and BAT and white adipose tissue (WAT) biopsies. BAT volume was significantly associated with increased whole-body lipolysis, triglyceride-free fatty acid (FFA) cycling, FFA oxidation, and adipose tissue insulin sensitivity. Functional analysis of BAT and WAT demonstrated the greater thermogenic capacity of BAT compared to WAT, while molecular analysis revealed a cold-induced upregulation of genes involved in lipid metabolism only in BAT. The accelerated mobilization and oxidation of lipids upon BAT activation supports a putative role for BAT in the regulation of lipid metabolism in humans.
Liver Med23 ablation improves glucose and lipid metabolism through modulating FOXO1 activity.
Chu Yajing,Gómez Rosso Leonardo,Huang Ping,Wang Zhichao,Xu Yichi,Yao Xiao,Bao Menghan,Yan Jun,Song Haiyun,Wang Gang
Mediator complex is a molecular hub integrating signaling, transcription factors, and RNA polymerase II (RNAPII) machinery. Mediator MED23 is involved in adipogenesis and smooth muscle cell differentiation, suggesting its role in energy homeostasis. Here, through the generation and analysis of a liver-specific Med23-knockout mouse, we found that liver Med23 deletion improved glucose and lipid metabolism, as well as insulin responsiveness, and prevented diet-induced obesity. Remarkably, acute hepatic Med23 knockdown in db/db mice significantly improved the lipid profile and glucose tolerance. Mechanistically, MED23 participates in gluconeogenesis and cholesterol synthesis through modulating the transcriptional activity of FOXO1, a key metabolic transcription factor. Indeed, hepatic Med23 deletion impaired the Mediator and RNAPII recruitment and attenuated the expression of FOXO1 target genes. Moreover, this functional interaction between FOXO1 and MED23 is evolutionarily conserved, as the in vivo activities of dFOXO in larval fat body and in adult wing can be partially blocked by Med23 knockdown in Drosophila. Collectively, our data revealed Mediator MED23 as a novel regulator for energy homeostasis, suggesting potential therapeutic strategies against metabolic diseases.
Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.
Ye Risheng,Gordillo Ruth,Shao Mengle,Onodera Toshiharu,Chen Zhe,Chen Shiuhwei,Lin Xiaoli,SoRelle Jeffrey A,Li Xiaohong,Tang Miao,Keller Mark P,Kuliawat Regina,Attie Alan D,Gupta Rana K,Holland William L,Beutler Bruce,Herz Joachim,Scherer Philipp E
The Journal of clinical investigation
The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.
Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism.
Duparc Thibaut,Plovier Hubert,Marrachelli Vannina G,Van Hul Matthias,Essaghir Ahmed,Ståhlman Marcus,Matamoros Sébastien,Geurts Lucie,Pardo-Tendero Mercedes M,Druart Céline,Delzenne Nathalie M,Demoulin Jean-Baptiste,van der Merwe Schalk W,van Pelt Jos,Bäckhed Fredrik,Monleon Daniel,Everard Amandine,Cani Patrice D
OBJECTIVE:To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. DESIGN:To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of . We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). RESULTS:Hepatocyte-specific deletion of predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. CONCLUSIONS:Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.