ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 15 OC23

Obesity resulting from Gs[alpha]; mutations in the maternal (but not paternal) allele is a consequence of Gsa; imprinting in the central nervous system

Min Chen, Kathryn Dickerson, Jie Wang, James Kelleher, Oksana Gavrilova, Qing-Hong Zhang, Tao Xie & Lee Weinstein


NIDDK, NIH, Bethesda, Maryland 20854, USA.


Gsα is a ubiquitously expressed G protein α-subunit that couples receptors to adenylyl cyclase and cAMP generation. In patients with Albright hereditary osteodystrophy (AHO), heterozygous Gsα mutations only lead to obesity when present on the maternal allele. Similarly, mice with heterozygous germline Gsα mutations on the maternal allele develop severe obesity and insulin resistance with reduced energy expenditure relative to food intake, while the effects of paternal Gsα mutations energy balance and glucose and lipid metabolism are minimal. These parent-of-origin-specific effects are likely due to the fact that Gsα is imprinted in a tissue-specific manner with preferential expression from the maternal allele in several tissues. To examine a potential role of Gsα imprinting in the central nervous system on the maternal-specific maternal-specific metabolic effects, we generated brain-specific Gsα heterozygotes in which the maternal (mBrGsKO) or paternal (pBrGsKO) Gsα allele was disrupted by mating Gsα-floxed mice with nestin-cre mice. After 6 weeks of age mBrGsKO developed severe obesity, hyperleptinemia, hyperglycemia, hypertriglyceridemia, glucose intolerance, and insulin resistance, associated with reduced energy expenditure and activity levels and reduced UCP1 expression in brown adipose tissue. In contrast, pBrGsKO mice did not show any of these metabolic features. In mBrGsKO mice the acute anorexic response to the melanocortin agonist MTII was unaffected, while these mice failed to acutely increase their energy expenditure in response to MTII. Both responses to MTII remained intact in pBrGsKO mice. These results strongly suggest that Gsα is imprinted in one or more CNS sites where it mediates the melanocortin signals required to increase energy expenditure. Gsα deficiency at these and perhaps other CNS sites likely underlies the obesity and other features of the metabolic syndrome that result from germline mutation of the maternal Gsα allele in mice and in AHO patients.

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