GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet.

We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically-optimized, PEGylated (PEG) leptin analog in combination with exendin-4 or FGF21. However, return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced co-agonism at the GLP-1 and glucagon receptors can restore leptin responsiveness in DIO mice maintained on HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce a ∼15% body weight loss, once upon they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared to PEG-GLP-1/glucagon alone, and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 co-treatment. In summary, we report that GLP-1/glucagon co-agonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value this polypharmacotherapy for the treatment of obesity and diabetes

Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like Peptide-1 receptor signaling

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