Paternal versus maternal transmission of a stimulatory G-protein α subunit knockout produces opposite effects on energy metabolism
Shuhua Yu, Oksana Gavrilova, Hui Chen, Randy Lee, Jie Liu, Karel Pacak, A.F. Parlow, Michael J. Quon, Marc L. Reitman, Lee S. Weinstein
Shuhua Yu, Oksana Gavrilova, Hui Chen, Randy Lee, Jie Liu, Karel Pacak, A.F. Parlow, Michael J. Quon, Marc L. Reitman, Lee S. Weinstein
View: Text | PDF
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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
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.