In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of G_sα, 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_sα 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_sα in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific G_sα-deficient mice by mating G_sα-floxed mice with SF1-cre mice. Heterozygotes with G_sα mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of G_sα imprinting, indicating that the parent-of-origin metabolic effects associated with G_sα mutations is not due to G_sα deficiency in VMH SF1 neurons. Homozygous VMH G_sα 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. In addition, 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 VMH G_sα/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake.