Gsα Deficiency in the Ventromedial Hypothalamus Enhances Leptin Sensitivity and Improves Glucose Homeostasis in Mice on a High-Fat Diet

In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of G(s)alpha, a ubiquitously expressed G protein that mediates receptor-stimulated intracellular cAMP production, lead to obesity and insulin resistance but only when the mutation is present on the maternal allele. This parent-of-origin effect in mice was shown to be due to G(s)alpha imprinting in one or more brain regions. The ventromedial hypothalamus (VMH) is involved in the regulation of energy and glucose homeostasis, but the role of G(s)alpha in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific G(s)alpha-deficient mice by mating G(s)alpha-floxed mice with SF1-cre mice. Heterozygotes with G(s)alpha mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of G(s)alpha imprinting, indicating that the parent-of-origin metabolic effects associated with G(s)alpha mutations is not due to G(s)alpha deficiency in VMH SF1 neurons. Homozygous VMH G(s)alpha knockout mice (VMHGsKO) showed no changes in body weight on either a regular or high-fat diet. However, glucose metabolism ( fasting glucose, glucose tolerance, insulin sensitivity) was significantly improved in male VMHGsKO mice, with the difference more dramatic on the high-fat diet. Inaddition, male VMHGsKO mice on the high-fat diet showed a greater anorexigenic effect and increased VMH signal transducer and activator of transcription-3 phosphorylation in response to leptin. These results indicate that VMHG(s)alpha/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake.