Endocrine Abstracts

G_sα 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 G_sα mutations only lead to obesity when present on the maternal allele. Similarly, mice with heterozygous germline G_sα mutations on the maternal allele develop severe obesity and insulin resistance with reduced energy expenditure relative to food intake, while the effects of paternal G_sα mutations energy balance and glucose and lipid metabolism are minimal. These parent-of-origin-specific effects are likely due to the fact that G_sα is imprinted in a tissue-specific manner with preferential expression from the maternal allele in several tissues. To examine a potential role of G_sα imprinting in the central nervous system on the maternal-specific maternal-specific metabolic effects, we generated brain-specific G_sα heterozygotes in which the maternal (mBrGsKO) or paternal (pBrGsKO) G_sα allele was disrupted by mating G_sα-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 G_sα is imprinted in one or more CNS sites where it mediates the melanocortin signals required to increase energy expenditure. G_sα 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 G_sα allele in mice and in AHO patients.