Paternal versus maternal transmission of a stimulatory G-protein α subunit knockout produces opposite effects on energy metabolism
Shuhua Yu, … , Marc L. Reitman, Lee S. Weinstein
Shuhua Yu, … , Marc L. Reitman, Lee S. Weinstein
Published March 1, 2000
Citation Information: J Clin Invest. 2000;105(5):615-623. https://doi.org/10.1172/JCI8437.
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Article

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

Abstract

Heterozygous disruption of Gnas, the gene encoding the stimulatory G-protein α subunit (Gsα), leads to distinct phenotypes depending on whether the maternal (m–/+) or paternal (+/p–) allele is disrupted. Gsα 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.

Authors

Shuhua Yu, Oksana Gavrilova, Hui Chen, Randy Lee, Jie Liu, Karel Pacak, A.F. Parlow, Michael J. Quon, Marc L. Reitman, Lee S. Weinstein

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Food intake and metabolic studies in m–/+ and +/p– mice. (a) Food intake...
Food intake and metabolic studies in m–/+ and +/p– mice. (a) Food intake in 6- to 8-week-old male mice over a 7-day period normalized to (body weight)0.75 (60–62). Data for mutant mice are shown as open bars, and data for wild-type mice are shown as filled bars (n = 6–8 mice per group). (b) Resting oxygen consumption at 21° C in 7-month-old female mice measured over a 24-hour period (n = 5 pairs of mice in each group). (c) Total and ambulating activity measured over 24 hours in mice studied in b. (d) Resting oxygen consumption at 30° C of 6- to 8-week-old female mice before (filled bars) and after (open bars) administration of a maximal dose of CL316243 (1,000 μg/kg intraperitoneally; n = 5 mice per group). For each group, the metabolic rate in the absence of agonist expressed as a percent of maximal metabolic rate is shown above. (e) Resting oxygen consumption in 6- to 8-week-old female m–/+ (open bars) and wild-type littermates (filled bars; n = 5 pairs) at 21° C is shown at the left. To the right is resting oxygen consumption in similar mice at 30° C treated with the indicated intraperitoneal doses of CL316243 (n = 4–10 pairs of mice at each dose). (f) Serum FFAs (left panel) and glycerol (right panel) in 6-hour fasted 13-week-old male m–/+ mice (open bars) and wild-type littermates (filled bars) before and 15 minutes after administration of a maximal dose of CL316243 (1,000 μg/kg intraperitoneally; n = 5 mice per group). In all panels, data are expressed as the mean ± SEM, and an asterisk indicates P < 0.05 versus wild-type littermates by t test.