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

ABSTRACT 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.

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Available from: Christelle Veyrat-Durebex, Sep 28, 2015
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    • "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"
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    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
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    • "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]. "
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    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
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    • "A central player involved in BAT activation is the hypothalamus, which projects onto sympathetic nerves that densely innervate BAT [2]. Various circulating peptides have been shown to be capable of activating BAT via the hypothalamus, such as GLP-1 [28] and BMP8B, another member of the BMP family [29]. In addition, Townsend et al. [25] showed that central administration of BMP7 resulted in reduced food intake, confirming that BMP7 is at least capable of exerting central effects. "
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    ABSTRACT: Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP-1 and is a promising target to combat hyperlipidemia and obesity. BAT is densely innervated by the sympathetic nervous system, which increases BAT differentiation and activity upon cold exposure. Recently, Bone Morphogenetic Protein 7 (BMP7) was identified as an inducer of BAT differentiation. We aimed to elucidate the role of sympathetic activation in the effect of BMP7 on BAT by treating mice with BMP7 at varying ambient temperature, and assessed the therapeutic potential of BMP7 in combating obesity. High-fat diet fed lean C57Bl6/J mice were treated with BMP7 via subcutaneous osmotic minipumps for 4 weeks at 21°C or 28°C, the latter being a thermoneutral temperature in which sympathetic activation of BAT is largely diminished. At 21°C, BMP7 increased BAT weight, increased the expression of Ucp1, Cd36 and hormone-sensitive lipase in BAT, and increased total energy expenditure. BMP7 treatment markedly increased food intake without affecting physical activity. Despite that, BMP7 diminished white adipose tissue (WAT) mass, accompanied by increased expression of genes related to intracellular lipolysis in WAT. All these effects were blunted at 28°C. Additionally, BMP7 resulted in extensive 'browning' of WAT, as evidenced by increased expression of BAT markers and the appearance of whole clusters of brown adipocytes via immunohistochemistry, independent of environmental temperature. Treatment of diet-induced obese C57Bl6/J mice with BMP7 led to an improved metabolic phenotype, consisting of a decreased fat mass and liver lipids as well as attenuated dyslipidemia and hyperglycemia. Together, these data show that BMP7-mediated recruitment and activation of BAT only occurs at subthermoneutral temperature, and is thus likely dependent on sympathetic activation of BAT, and that BMP7 may be a promising tool to combat obesity and associated disorders.
    PLoS ONE 09/2013; 8(9):e74083. DOI:10.1371/journal.pone.0074083 · 3.23 Impact Factor
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