THU127 Deletion Of VGLUT2 In MCH Neurons Induces Sex-Specific Changes In Metabolic And Reproductive Function

Disclosure: B.G. Beekly: None. MCH neurons have a well-established role in metabolism and energy balance. MCH-knockout (“MCH-KO”) mice, which lack the MCH peptide itself, are hyperactive, hypophagic, and lean. However, MCH neurons express numerous genes involved in the synthesis, packaging, and release of the classical neurotransmitters GABA and glutamate, which are the central nervous system’s predominant inhibitory and excitatory neurotransmitters, respectively. These genes are also critical for normal metabolism, as the conditional deletion of glutamatergic signaling from MCH neurons also affects energy balance in ways that both mirror and differ from MCH-KO. When the metabolic phenotypes of MCH neuronal ablation (diphtheria toxin), MCH-KO, and transgenic Pmch-Cre;Slc17a6(fl/fl) mice (which lack VGLUT2 in MCH neurons) are compared, all three experimental groups exhibit decreased body weight and adiposity, increased locomotor activity, late-onset hypophagia, attenuated weight gain on high-fat diet, and reductions in circulating leptin. These data point to some functional redundancy between MCH and glutamate release from MCH neurons in the context of energy balance. By contrast, specific indicators of glucose sensing and handling differ between groups: MCH neuronal ablation and conditional VGLUT2 deletion in MCH neurons, but not global MCH-KO, result in reduced sucrose preference and improved glucose tolerance. These data suggest a role for MCH peptide in body weight regulation, but also a glutamate-dependent mechanism by which MCH neurons contribute to glucose homeostasis. Given the findings related to MCH peptide action on pancreatic islet cells and its effects on insulin resistance, it appears that MCH and glutamatergic signaling from MCH neurons must work synergistically for optimal regulation of energy balance. Importantly, all research to date on the metabolic effect of VGLUT2 deletion from MCH neurons has been in male mice. This constitutes a significant gap in the field’s understanding of these phenomena, particularly because of documented sex differences in glucose handling and associated metabolic disorders like diabetes. To address these gap, we generated Pmch-Cre;Slc17a6(fl/fl) mice, which lack functional VGLUT2 in MCH neurons. Body weight was measured from weaning until 20 weeks of age and the mice were subjected to comprehensive metabolic testing including oral glucose tolerance testing. We were able to recapitulate some, but not all, of the published findings in males, a fact which may in large part be due to strain differences in metabolism and glucose handling. Notably, several sexually dimorphic phenotypes were also observed, reaffirming the importance of incorporating biological sex variables into metabolic studies. Presentation: Thursday, June 15, 2023