Direct Control of Brown Adipose Tissue Thermogenesis by Central Nervous System Glucagon-Like Peptide-1 Receptor Signaling

Corresponding author: Diego Perez-Tilve, .
Diabetes (Impact Factor: 8.1). 08/2012; 61(11):2753-62. DOI: 10.2337/db11-1556
Source: PubMed


We studied interscapular brown adipose tissue (iBAT) activity in wild-type (WT) and glucagon-like peptide 1 receptor (GLP-1R)-deficient mice after the administration of the proglucagon-derived peptides (PGDPs) glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) directly into the brain. Intracerebroventricular injection of PGDPs reduces body weight and increases iBAT thermogenesis. This was independent of changes in feeding and insulin responsiveness but correlated with increased activity of sympathetic fibers innervating brown adipose tissue (BAT). Despite being a GCG receptor agonist, OXM requires GLP-1R activation to induce iBAT thermogenesis. The increase in thermogenesis in WT mice correlates with increased expression of genes upregulated by adrenergic signaling and required for iBAT thermogenesis, including PGC1a and UCP-1. In spite of the increase in iBAT thermogenesis induced by GLP-1R activation in WT mice, Glp1r(-/-) mice exhibit a normal response to cold exposure, demonstrating that endogenous GLP-1R signaling is not essential for appropriate thermogenic response after cold exposure. Our data suggest that the increase in BAT thermogenesis may be an additional mechanism whereby pharmacological GLP-1R activation controls energy balance.

Download full-text


Available from: Christelle Veyrat-Durebex,
  • Source
    • "The AP and SFO, which form part of the brains' circumventricular organs, also contained large numbers of GLP-1R expressing cells. Moderate numbers of GLP-1R expressing cells were observed in the ventrolateral medulla, which like the PVN harbours presympathetic neurons, and thus both regions might contribute to the effects of GLP-1 on cardiovascular control as well as thermogenesis [8] [9] [33]. Of particular interest were brain areas such as the VTA and NAc, which have recently received attention for their ability to reduce food intake and reward behaviour following GLP-1R activation [10] [34] [35]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Although Glucagon-like peptide 1 is a key regulator of energy metabolism and food intake, the precise location of GLP-1 receptors and the physiological relevance of certain populations is debatable. This study investigated the novel GLP-1R-Cre mouse as a functional tool to address this question. Methods: Mice expressing Cre-recombinase under the Glp1r promoter were crossed with either a ROSA26 eYFP or tdRFP reporter strain to identify GLP-1R expressing cells. Patch-clamp recordings were performed on tdRFP-positive neurons in acute coronal brain slices from adult mice and selective targeting of GLP-1R cells in vivo was achieved using viral gene delivery. Results: Large numbers of eYFP or tdRFP immunoreactive cells were found in the circumventricular organs, amygdala, hypothalamic nuclei and the ventrolateral medulla. Smaller numbers were observed in the nucleus of the solitary tract and the thalamic paraventricular nucleus. However, tdRFP positive neurons were also found in areas without preproglucagon-neuronal projections like hippocampus and cortex. GLP-1R cells were not immunoreactive for GFAP or parvalbumin although some were catecholaminergic. GLP-1R expression was confirmed in whole-cell recordings from BNST, hippocampus and PVN, where 100 nM GLP-1 elicited a reversible inward current or depolarisation. Additionally, a unilateral stereotaxic injection of a cre-dependent AAV into the PVN demonstrated that tdRFP-positive cells express cre-recombinase facilitating virally-mediated eYFP expression. Conclusions: This study is a comprehensive description and phenotypic analysis of GLP-1R expression in the mouse CNS. We demonstrate the power of combining the GLP-1R-CRE mouse with a virus to generate a selective molecular handle enabling future in vivo investigation as to their physiological importance.
    Molecular Metabolism 08/2015; 4(10). DOI:10.1016/j.molmet.2015.07.008
  • Source
    • "In addition to causing changes in feeding , central GLP - 1R activa - tion may regulate body weight by increasing brown adipose tissue ( BAT ) thermogenesis ( reviewed in Lockie et al . , 2013 ) . Chronic ICV administration of oxyntomodulin , a GLP - 1R agonist , in mice decreased body weight despite having no significant effects on food intake ( Lockie et al . , 2012 ) . Interestingly , BAT temperature was increased in these animals , which may have contributed to the weight loss . The effect of oxyntomodulin on body weight and BAT temperature is not evident in mice that lack the GLP - 1R highlighting a GLP - 1R dependent action . To determine the site of GLP - 1R mediated action on BAT thermogenesi"
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.
    Frontiers in Neuroscience 03/2015; 9:92. DOI:10.3389/fnins.2015.00092 · 3.66 Impact Factor
  • Source
    • "A potential mechanism that could also be involved in the anti-obesity effects of oxyntomodulin is the direct effect of glucagon on brown adipose tissue associated with the adrenergic GLP1R-dependent stimulation of adipose tissue thermogenesis [84]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) resulting in superior body weight lowering to selective GLP1R agonists. OXM reduces food intake and increases energy expenditure in humans. While activation of the GCGR increases glucose production posing a hyperglycemic risk, the simultaneous activation of the GLP1R counteracts this effect. Acute OXM infusion improves glucose tolerance in T2DM patients making dual agonists of the GCGR and GLP1R new promising treatments for diabetes and obesity with the potential for weight loss and glucose lowering superior to that of GLP1R agonists.
    Molecular Metabolism 06/2014; 3(3):241-251. DOI:10.1016/j.molmet.2013.12.001
Show more