Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism

• Published in: The Journal of clinical investigation Vol. 105; no. 5; pp. 615 - 623
• Main Authors: Yu, S, Gavrilova, O, Chen, H, Lee, R, Liu, J, Pacak, K, Parlow, A F, Quon, M J, Reitman, M L, Weinstein, L S
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-03-2000
• Subjects: Adrenergic beta-Agonists - pharmacology; Alleles; Animals; Body Weight; Dioxoles - pharmacology; Energy Metabolism; Female; Genomic Imprinting; GTP-Binding Protein alpha Subunits, Gs - deficiency; GTP-Binding Protein alpha Subunits, Gs - genetics; Histocytochemistry; Leptin - blood; Lipids - blood; Male; Mice; Mice, Knockout; Obesity - blood; Obesity - genetics; Phenotype; Thyroid Hormones - blood; Thyrotropin - blood
• ISSN: 0021-9738
• DOI: 10.1172/JCI8437

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.