MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Enhances Leptin-Mediated pSTAT3 Induction in Key Neuronal Regions That Regulate Metabolism

MEDI0382 is a potent GLP-1 and glucagon receptor dual agonist peptide that decreases body weight of obese mice by reducing food intake and enhancing energy expenditure. Here we explored whether MEDI0382 may, in part, mediate its effects on metabolism by enhancing leptin action. Diet-induced obese mice were administered vehicle, MEDI0382 (10 nmol/kg; s.c., q.d.) or vehicle and pair-fed to MEDI0382-treated mice for 10 days (n=15-16/group). During this period MEDI0382 induced 11% body weight loss (p<0.01 vs. vehicle), whereas pair-fed mice lost a similar amount of body weight as MEDI0382 group for first 5 days, but rebounded such that final weight loss was 3% from baseline (p<0.vs. vehicle and MEDI0382). On day 10, half of each group was administered vehicle (PBS) or murine leptin (10 mg/kg) and the mice sacrificed 45 min later. Leptin administration increased circulating leptin levels 20-25-fold above endogenous levels. Levels of phosphorylated STAT3 (pSTAT3), a key marker of leptin signaling, were determined in discrete nuclei of the hypothalamus known to regulate energy homeostasis. Within the arcuate nucleus of the hypothalamus pSTAT3 levels were not significantly stimulated by leptin in vehicle or pair-fed mice (indicative of leptin resistance), but were increased in MEDI0382-treated animals. Furthermore, in the dorsomedial, ventromedial and lateral hypothalamic nuclei leptin was able to stimulate pSTAT3 in vehicle and pair-fed mice, but in MEDI0382-treated mice pSTAT3 levels were even further enhanced (p<0.vs. other leptin-treated groups). While we cannot exclude weight loss per se as a factor, these data support the notion that MEDI0382 may mediate its effects on body weight and glycemic control via enhancing central leptin action.