title: Gsα Deficiency in the Ventromedial Hypothalamus Enhances Leptin Sensitivity and Improves Glucose Homeostasis in Mice on a High-Fat Diet.
abstract: In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of Gsα, 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 Gsα 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 Gsα in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific Gsα-deficient mice by mating Gsα-floxed mice with SF1-cre mice. Heterozygotes with Gsα mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of Gsα imprinting, indicating that the parent-of-origin metabolic effects associated with Gsα mutations is not due to Gsα deficiency in VMH SF1 neurons. Homozygous VMH Gsα 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 Gsα/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Alta
authors.initials: A
authors.lastname: Berger
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kablan
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Catherine
authors.initials: C
authors.lastname: Yao
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Thuy
authors.initials: T
authors.lastname: Ho
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Brandon
authors.initials: B
authors.lastname: Podyma
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004351:Drug Resistance / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism*
chemical_list: D020738:Leptin; D019205:GTP-Binding Protein alpha Subunits, Gs; D005947:Glucose