MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Acutely Inhibits Food Intake in Leptin-Deficient ob/ob Mice and Leptin Receptor–Deficient fa/fa Rats

Abstract

MEDI0382 is a potent glucagon-like-peptide-1 (GLP-1) and glucagon receptor dual agonist that inhibits feeding and induces weight loss in mice. To test whether MEDI0382-mediated improvements in metabolism require leptin signaling, we determined its acute effects on food intake in rodents lacking either leptin (ob/ob mice) or the leptin receptor (fa/fa rats). An acute dose response study in ob/ob mice was performed with mice dosed subcutaneously (SC) with GLP-1 receptor agonist liraglutide (30 nmol/kg), glucagon receptor agonist G1437 (30 nmol/kg), or MEDI0382 (1, 3, 10 or 30 nmol/kg). At 24 h, liraglutide and G1437 treatment reduced food intake by 50% and 16% vs. controls, respectively. MEDI0382 inhibited food intake in a dose-dependent manner, and exerted superior inhibition of food intake compared to equimolar doses of liraglutide and G1437. The fa/fa rats were also dosed once with liraglutide, G1437 (both at same doses as above), or MEDI0382 (3, 10 and 30 nmol/kg) and food intake measured. Liraglutide and G1437 treatment decreased 24 h food intake by 55% and 27% respectively and MEDI0382 dose-dependently decreased food intake (32%, 67% and 77%). Also, fa/fa rats treated with MEDI0382 had an additional reduction in food intake than equimolar doses of either liraglutide or G1437. Finally, lean C57BL/6 mice housed in the BioDaq food intake monitoring system were dosed SC once with MEDI0382 (0.3, 1, 3, 10 and 30 nmol/kg), and a dose-dependent effect on inhibition of food intake was observed. Further analysis showed MEDI0382 decreased total meal number and increased satiety ratio. In summary, MEDI0382 exerted potent anorexigenic effects in mice independent of the leptin pathway, characterized by decreased number of meals consumed and increased satiety. Disclosure V.G. Howard: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Regeneron Pharmaceuticals, Inc., AstraZeneca. S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. A. Konkar: Employee; Self; Sanofi. Other Relationship; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.