Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Nogueiras, Rubén; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A.; Varela, Luis; Haynes, William G.; Patterson, James T.; Disse, Emmanuel; Pfluger, Paul T.; López, Miguel; Woods, Stephen C.; DiMarchi, Richard D.; Diéguez, Carlos; Rahmouni, Kamal; Rohner‐Jeanrenaud, Françoise; Tschöp, Matthias H.

doi:10.1523/jneurosci.5977-08.2009

Cited by 149 publications

(148 citation statements)

References 54 publications

(57 reference statements)

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“…Moreover, others have demonstrated that acute activation of central nervous system (CNS) GLP-1Rs promotes BAT thermogenesis and WAT browning [36][37][38]. However, browning of WAT induced by CNS infusion of GLP-1R agonist was abolished in mice with diet-induced obesity [36,38]. We observed that chronic peripheral treatment with GLP-1R agonist promoted the browning of WAT in diet-induced obese mice.…”

Section: Discussionmentioning

confidence: 57%

“…Our data A clinical study revealed that a dipeptidyl peptidase-4 (DPP-4) inhibitor that decreases endogenous GLP-1 degradation augmented adipose tissue lipolysis and the rate of systemic lipid oxidation in type 2 diabetic patients [35]. Moreover, others have demonstrated that acute activation of central nervous system (CNS) GLP-1Rs promotes BAT thermogenesis and WAT browning [36][37][38]. However, browning of WAT induced by CNS infusion of GLP-1R agonist was abolished in mice with diet-induced obesity [36,38].…”

Section: Discussionmentioning

confidence: 71%

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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: 57%

Section: Discussionmentioning

confidence: 71%

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

et al. 2016

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“…Fat mobilization is normally mediated via increased activities of the SNS [31,32]. Increased release of NE from sympathetic nerves activates Adrb3 on the surface of adipocytes, increasing intracellular levels of cAMP that activates PKA, which mediates phosphorylation and activation of HSL [33,34].…”

Section: Discussionmentioning

confidence: 99%

ATF4 regulates lipid metabolism and thermogenesis

et al. 2010

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Activating transcription factor 4 (ATF4) has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4-deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 (UCP2) and β-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue (WAT), suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue (BAT), suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.

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“…Seven to 11 animals per group were used. Tenweek-old WT and TKO mice were obtained as previously described (13)(14)(15) …”

Section: Animals and Dietsmentioning

confidence: 99%

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

et al. 2015

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The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.After the ingestion of a meal, the presence of nutrients in the gastrointestinal (GI) tract initiates complex neural and hormonal responses that send signals to the brain about the ongoing changes in nutritional status. Among the different strategies used to communicate to the brain, the gut secretes peptides that reach the central nervous system (CNS) via afferent nerve fibers or the circulation (1,2). New gut hormones are continuously discovered, and, with the exception of ghrelin, which is the only peptidic hormone favoring weight gain and adiposity, all of them are associated with a negative energy balance and are thus potential targets for the treatment of obesity (3,4).One of the most recently discovered gut hormones is uroguanylin (UGN), a 16-amino acid peptide secreted mainly from duodenal epithelial cells. UGN is synthesized as a prohormone (pro-UGN), which, after cleavage by a still unknown enzyme, is converted to the active UGN (3,5). Both pro-UGN and UGN activate the guanilate cyclase 2C receptor (GUCY2C), which is also targeted by diarrheagenic bacterial heat-stable enterotoxins (STs) (6). The activation of GUCY2C leads to elevated intracellular levels of cyclic guanosine monophosphate (7), which in invertebrate species has been demonstrated to lead to alterations in food behavior and energy-balance regulation (8,9). Circulating UGN levels were decreased in fasted and leptin-deficient mice but recovered after refeeding or exogenous leptin

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Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

Cited by 149 publications

References 54 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

ATF4 regulates lipid metabolism and thermogenesis

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

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