Hypothalamic Glucagon Receptors Regulate Feeding in Mice

Glucagon is an essential regulator of glucose and lipid metabolism. We have reported that chronic glucagon receptor (GCGR) activation with the highly selective, long-acting GCGR-agonist, IUB288, promotes weight-loss by stimulating energy expenditure and suppressing food intake in diet-induced obese (DIO) mice. Thus, novel therapeutics that include glucagon receptor (GCGR) agonism have emerged as promising candidates for obesity and diabetes. GCGR-stimulated energy expenditure is predominately dependent on hepatic GCGR activation; however, the tissue(s) responsible for GCGR-dependent suppression of food intake have yet to be elucidated. Intriguingly, intracerebroventricularly (ICV) injected glucagon acutely suppresses food intake, suggesting neurons expressing GCGR in the brain mediate the anorectic actions of GCGR activation. Hypothalamic neurons express appetitive neuropeptides, sense nutrients in circulation, and respond to peripheral endocrine signals. Studies herein, utilize mice with hypothalamic Gcgr-deficiency (Gcgr(ΔHypo)) to test the hypothesis that peripherally administered GCGR-agonists (e.g. IUB288) reverse obesity via their actions on hypothalamic GCGRs to suppress food intake and concurrent hepatic effects on energy expenditure. Gcgr(ΔHypo) and littermate control mice were fasted overnight to stimulate endogenous hunger signals and test for differential food intake upon refeeding. Interestingly, lean, male Gcgr(ΔHypo) mice displayed acute hyperphagia in comparison to control littermates. Gcgr(ΔHypo) mice also displayed elevated locomotor activity, an increase in the respiratory exchange ratio, and elevated energy expenditure compared to littermate controls. Furthermore, these metabolic alterations are associated with delayed body weight gain and chronic hyperphagia in Gcgr(ΔHypo) mice allowed ad libitum access to a high fat diet for 12 weeks. Consistent with our hypothesis, chronic peripheral administration of IUB288 (14d i.p.) suppressed food intake in DIO male control, but not Gcgr(ΔHypo), mice. Altogether, these data suggest that hypothalamic GCGRs mediate the anorectic actions of GCGR activation and play a regulatory role in food take. Moreover, these findings suggest that GCGR-based therapeutics may act on both intake and expenditure components of energy balance to combat obesity.