GCGR agonism requires GABAergic signaling in the medial basal hypothalamus to promote weight loss in obese mice.

Glucagon receptor (GCGR)-mediated thermogenesis is a key component for the next-generation of obesity therapeutics. Herein, we investigated the central and peripheral mechanism by which activation of the GCGR augments metabolic rate to promote weight loss. Chronic treatment of obese mice with a long-acting GCGR agonist (LAGCGRA) reduced body weight and fat mass at both room temperature and thermoneutrality. Metabolic cage studies highlight that whilst GCGR agonism induces a negative energy balance via effects on both sides of energy balance, weight loss is primarily due to augmented metabolic rate in obese mice. Mechanistically, we report for the first time that GCGR agonism recruits GABAergic signaling in the medial basal hypothalamus to promote uncoupling protein 1(UCP1)-dependent thermogenesis in adipose tissue, stimulate caloric expenditure, and drive a negative energy balance in obese mice. Our preclinical findings provide insight in to how multi-receptor agonists engaging the GCGR may function to improve the weight loss efficacy of anorectic agents. Collectively, our results point to a liver→brain→fat axis activated by GCGR agonism for weight loss in obesity. Future studies are required to validate our findings in the clinic.