title: Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism.
abstract: Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein alpha subunit (G(s)alpha), leads to distinct phenotypes depending on whether the maternal (m-/+) or paternal (+/p-) allele is disrupted. G(s)alpha is imprinted, with the maternal allele preferentially expressed in adipose tissue. Hence, expression is decreased in m-/+ mice but normal in +/p- mice. M-/+ mice become obese, with increased lipid per cell in white and brown adipose tissue, whereas +/p- mice are thin, with decreased lipid in adipose tissue. These effects are not due to abnormalities in thyroid hormone status, food intake, or leptin secretion. +/p- mice are hypermetabolic at both ambient temperature (21 degrees C) and thermoneutrality (30 degrees C). In contrast, m-/+ mice are hypometabolic at ambient temperature and eumetabolic at thermoneutrality M-/+ and wild-type mice have similar dose-response curves for metabolic response to a beta(3)-adrenergic agonist, CL316243, indicating normal sensitivity of adipose tissue to sympathetic stimulation. Measurement of urinary catecholamines suggests that +/p- and m-/+ mice have increased and decreased activation of the sympathetic nervous system, respectively. This is to our knowledge the first animal model in which a single genetic defect leads to opposite effects on energy metabolism depending on parental inheritance. This probably results from deficiency of maternal- and paternal-specific Gnas gene products, respectively.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.forename: O
authors.initials: O
authors.lastname: Gavrilova
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Pacak
authors.forename: A F
authors.initials: AF
authors.lastname: Parlow
authors.forename: M J
authors.initials: MJ
authors.lastname: Quon
authors.forename: M L
authors.initials: ML
authors.lastname: Reitman
authors.forename: L S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D001835:Body Weight; D004149:Dioxoles / Q000494:pharmacology; D004734:Energy Metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics*; D018392:Genomic Imprinting; D006651:Histocytochemistry; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000235:genetics*; D010641:Phenotype; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood
chemical_list: D000318:Adrenergic beta-Agonists; D004149:Dioxoles; D020738:Leptin; D008055:Lipids; D013963:Thyroid Hormones; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D013972:Thyrotropin; D019205:GTP-Binding Protein alpha Subunits, Gs