The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice

Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD(ΔNkx2.1cre)). We also generated mice lacking Glp1r expression specifically in two GLP-1RA–responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD(ΔSim1cre)) and proopiomelanocortin neurons (GLP-1RKD(ΔPOMCcre)). Chow-fed GLP-1RKD(ΔNkx2.1cre) mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD(ΔSim1cre) and GLP-1RKD(ΔPOMCcre) mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD(ΔNkx2.1cre) mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.