SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL

Chakrabarti, Partha; English, Taylor; Karki, Shakun; Li, Qiang; Tao, Rong; Kim, Juyoun; Luo, Zhijun; Farmer, Stephen R.; Kandror, Konstantin V.

doi:10.1194/jlr.m014647

Cited by 151 publications

(106 citation statements)

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“…SIRT1 promotes lipolysis in adipocytes via activation of the rate-limiting lipolytic enzyme ATGL [14]. Here, we found that exenatide (exendin-4) reduced adiposity by activating SIRT1 and consequently upregulating ATGL.…”

Section: Discussionmentioning

confidence: 56%

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GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

et al. 2016

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Aims/hypothesis Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in weight loss. Sirtuin 1 (SIRT1) plays a vital role in the regulation of lipid metabolism. Here, we investigated the contribution of lipolytic and oxidative changes in white adipose tissue (WAT) to the weight-lowering effect induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in mice. We also looked at the role of SIRT1 in this process. Methods C57BL/6J mice and Sirt1 +/− mice were treated with exenatide (24 nmol/kg) or an NaCl solution (154 mmol/l) control i.p. for 8 weeks while receiving a high-fat diet (HFD) after a 12 week HFD challenge. Systemic phenotypic evaluations were carried out during and after the intervention. A lentivirus-mediated short hairpin (sh)RNA vector of the Sirt1 gene was transfected into differentiated 3T3-L1 adipocytes. An in vitro model system used adipocytes induced from Sirt1-null mouse embryonic fibroblasts (MEFs). Results Exenatide reduced fat mass and enhanced the lipolytic and oxidative capacity of WAT in diet-induced obese C57BL/ 6J mice. However, these effects were significantly impaired in Sirt1 +/− mice compared with wild-type controls. In vitro, exendin-4 increased lipolysis and fatty acid oxidation by upregulating SIRT1 expression and activity in differentiated 3T3-L1 adipocytes. Conversely, RNA interference (i)-induced knockdown of SIRT1 attenuated the lipolytic and oxidative responses to exendin-4 in differentiated 3T3-L1 adipocytes. Again, these responses were entirely abolished in Sirt1-null MEFs after induction into adipocytes. Conclusions/interpretation These data highlight that a GLP-1R agonist promotes brown remodelling of WAT in a SIRT1-dependent manner; this might be one of the mechanisms underlying its effect on weight loss.

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Section: Discussionmentioning

confidence: 56%

“…Increased SIRT1 activity leads to the activation of adipose triacylglycerol lipase (ATGL), with subsequent triacylglycerol depletion of WAT [14]. Moreover, overexpression of SIRT1 in WAT effected a reduction of fat accumulation in adipocytes, with improved whole-body energy expenditure [15].…”

Section: Introductionmentioning

confidence: 99%

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

et al. 2016

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“…FOXOs are typically associated with the transcription of genes downstream to insulin/insulin-like growth factor (IGF) signaling, which include lipogenic and lipolytic genes (14, 15). Although SIRT1 regulates FOXO-dependent transcription (16), the importance of the SIRT1-FOXO cross talk in mediating the effects of insulin signaling at the organismal level is poorly addressed (17)(18)(19). In this respect, it is important to delineate the Sir2/SIRT1-dependent fat phenotype from insulin resistance in the liver and in peripheral tissues (muscles), in addition to investigating the role of FOXO in regulating these effects.…”

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confidence: 99%

Fat Body dSir2 Regulates Muscle Mitochondrial Physiology and Energy Homeostasis Nonautonomously and Mimics the Autonomous Functions of dSir2 in Muscles

Banerjee

Ayyub

Sengupta

et al. 2013

Molecular and Cellular Biology

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Sir2 is an evolutionarily conserved NAD؉ -dependent deacetylase which has been shown to play a critical role in glucose and fat metabolism. In this study, we have perturbed Drosophila Sir2 (dSir2) expression, bidirectionally, in muscles and the fat body. We report that dSir2 plays a critical role in insulin signaling, glucose homeostasis, and mitochondrial functions. Importantly, we establish the nonautonomous functions of fat body dSir2 in regulating mitochondrial physiology and insulin signaling in muscles. We have identified a novel interplay between dSir2 and dFOXO at an organismal level, which involves Drosophila insulinlike peptide (dILP)-dependent insulin signaling. By genetic perturbations and metabolic rescue, we provide evidence to illustrate that fat body dSir2 mediates its effects on the muscles via free fatty acids (FFA) and dILPs (from the insulin-producing cells [IPCs]). In summary, we show that fat body dSir2 is a master regulator of organismal energy homeostasis and is required for maintaining the metabolic regulatory network across tissues. Metabolic and energy homeostasis are tightly linked to insulin signaling and fat metabolism, which together become crucial determinants of organismal physiology (1, 2). From a clinical perspective, dysfunctions in insulin signaling and metabolic defects affect each other, as seen in obesity and type 2 diabetes (2, 3). Comorbidity of these conditions arises because abrogated fat metabolism has been implicated in insulin resistance and because alterations in insulin signaling are known to regulate the expression of fat metabolism genes. However, the interplay between insulin signaling, fat metabolism, and mitochondrial functions in the etiology of metabolic diseases is still unclear (4).Recent reports in mammals and flies clearly show that SIRT1/ Sir2 plays an important role in fat metabolism (5-12) and affects starvation survival (5). Additionally, ablation of SIRT1 in liver and muscles has been shown to result in an insulin resistance-like phenotype (12, 13). However, it is not clear if fat metabolism and systemic insulin signaling are regulated independently by Sir2/ SIRT1. An important link between insulin signaling and fat metabolism is the FOXO family of transcription factors. FOXOs are typically associated with the transcription of genes downstream to insulin/insulin-like growth factor (IGF) signaling, which include lipogenic and lipolytic genes (14, 15). Although SIRT1 regulates FOXO-dependent transcription (16), the importance of the SIRT1-FOXO cross talk in mediating the effects of insulin signaling at the organismal level is poorly addressed (17)(18)(19). In this respect, it is important to delineate the Sir2/SIRT1-dependent fat phenotype from insulin resistance in the liver and in peripheral tissues (muscles), in addition to investigating the role of FOXO in regulating these effects.Impaired insulin signaling has been associated with mitochondrial dysfunctions and defects in energy homeostasis. Several reports highlight the role of SIRT1 in affecti...

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“…SIRT1 is induced in several tissues during CR (18) and responds to the organism's need for energy by stimulating lipid breakdown through the transcription factor FoxO1, which directly induces expression of the rate-limiting lipolytic enzyme adipose triglyceride lipase (19). SIRT1 also inhibits cells' ability to synthesize fat by deacetylating the lipogenic activator SREBP-1c, preventing this factor from binding the promoters of lipogenic genes (20,21).…”

Section: Metabolismmentioning

confidence: 99%

From Sirtuin Biology to Human Diseases: An Update

Sebastián

Satterstrom

Haigis

et al. 2012

Journal of Biological Chemistry

208

159

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Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD ؉ -dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (1). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (3). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.Mammals have seven sirtuins (SIRT1-7) that possess NAD ϩ -dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (4). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3-5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology. AgingFollowing the first publication describing a role for yeast Sir2 in promoting longevity (2), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (5), although their role in worm and fly life span has recently been debated (6, 7). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR) 5 (8), a dietary intervention that robustly extends life span across numerous species. However, wholebody overexpression of SIRT1 in mice does not affect life span (9). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (10).The strongest link between mammalian sirtuins and the antiaging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (11). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral...

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SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL

Cited by 151 publications

References 64 publications

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1

Fat Body dSir2 Regulates Muscle Mitochondrial Physiology and Energy Homeostasis Nonautonomously and Mimics the Autonomous Functions of dSir2 in Muscles

From Sirtuin Biology to Human Diseases: An Update

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