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

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.

Targeting the gastrointestinal tract to treat type 2 diabetes

“…As a result, studies hypothesize that effects on insulin release, as well as other glucoregulatory effects of GLP-1, such as decreased glucose production, increased glucose utilization and regulation of counter-regulatory hormones, are mediated at least in part by a gut-brainperiphery axis (Burcelin et al 2001). Complicating this model further, GLP-1 can also act centrally to regulate food intake (Tang-Christensen et al 1996), energy expenditure (Lockie et al 2012), GI function (Seeley et al 2000) and importantly, glucose homeostasis (Knauf et al 2005, Gustavson et al 2008. However, in contrast to these studies, others suggest that the glucoregulatory effects of GLP-1 are primarily mediated by pancreatic GLP-1R activation (Lamont et al 2012, Smith et al 2014.…”

Non-sympathetic control of brown adipose tissue

“…40 Pro-glucagonderived peptides of intestinal origin (for example, GLP-1) have also been reported to activate BAT, but current evidence points to an indirect effect mediated by the central action of these peptides. 41 There are also reports indicating that fibroblast growth factor (FGF)-15/19, an endocrine factor released by the ileum and similar to FGF21 (see below), enhances BAT activity and overall energy expenditure. 42 Finally, signals of hepatic origin, including bile acids, have also been recognized to control BAT activity.…”

The color of fat and its central role in the development and progression of metabolic diseases

“…As obesity (both in humans and mice) is characterized by high plasma levels of FGF21 [99], [100], it is likely that the target tissues are resistant to the effect of this cytokine. Glucagon-like peptide (GLP-1), glucagon (GCG), and oxyntomodulin (OXM) have been also implicated in BAT activation and browning [101]. All these peptides originate from proglucagon and are involved in both glucose and lipid metabolism [102].…”

“…All these peptides originate from proglucagon and are involved in both glucose and lipid metabolism [102]. The administration of the GLP-1, GCG or OXM directly into the brain activates BAT and thermogenesis mainly through cerebral GLP-1 receptors [101], in particular those present in the hypothalamus [103]. GLP-1 receptor agonists (GLP-1 RA) therapy is associated with weight loss and both liraglutide and exenatide (two currently approved GLP-1 RA) have been shown to activate cerebral GLP-1R [56] and to increase energy expenditure [103].…”