H eterozygous disruption of Gnas, the gene encoding the stimulatory G-protein α subunit (G_sα), leads to distinct phenotypes depending on whether the maternal (m–/+) or paternal (+/p–) allele is disrupted. G_sα 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° C) and thermoneutrality (30° 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 β₃-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.