Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice

Abstract

Aims/hypothesisGlucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.MethodsLean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.ResultsCentral administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Conclusions/interpretationCollectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

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

“…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.…”

“…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].…”

Activation of murine pre-proglucagon–producing neurons reduces food intake and body weight

“…Interestingly, both an increase and decrease in metabolic rate have been reported, making it difficult to predict the actions of the endogenous GCG neuronal system. Chronic GLP-1 infusion into the CNS has been shown to lead to transcriptional activation of iBAT and glucose/triglyceride uptake (49,58) resulting from an increase in sympathetic outflow driven by GLP-1R signaling. Other data, however, have shown that the GLP-1R agonist EX-4 can also produce a lowering of VO 2 .…”

Is obesity a disease?

“…Hormoni digestivnog trakta poput GLP-1 posreduju efekte na unos hrane, potrošnju energije i infl amaciju. GLP-1 receptorski signaling aktivira BAT i promoviše braonizaciju WAT-a (19,20), dok GLP-1 takođe smanjuje infi ltraciju makrofazima i infl amatorni signaling u belim adipocitima i makrofagima (21,22). Druge hormonalne promene, kao što je menopauza, takođe utiču na energetski metabolizam.…”

“…Gut hormones such as GLP-1 mediate effects on food intake, energy expenditure and inflammation. GLP-1 receptor signaling activates BAT and promotes beiging of WAT (19,20) while GLP-1 also reduces macrophage infiltration and inflammatory signalling in white adipocytes and macrophages (21,22). Other hormonal changes such as menopause also affect energy metabolism.…”