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

J Clin Invest. 2000 Mar;105(5):615-23. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Alleles
  • Animals
  • Body Weight
  • Dioxoles / pharmacology
  • Energy Metabolism*
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / deficiency
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • Genomic Imprinting
  • Histocytochemistry
  • Leptin / blood
  • Lipids / blood
  • Male
  • Mice
  • Mice, Knockout
  • Obesity / blood
  • Obesity / genetics*
  • Phenotype
  • Thyroid Hormones / blood
  • Thyrotropin / blood


  • Adrenergic beta-Agonists
  • Dioxoles
  • Leptin
  • Lipids
  • Thyroid Hormones
  • disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
  • Thyrotropin
  • GTP-Binding Protein alpha Subunits, Gs