Thinking Thin with Mom’s Gα Gene

Science Signaling  09 Jun 2009:
Vol. 2, Issue 74, pp. ec197
DOI: 10.1126/scisignal.274ec197

A mutation in the Gα subunit of the heterotrimeric guanine nucleotide–binding protein (G protein) Gs, which transduces signals from various hormone receptors, causes obesity and insulin resistance in the human genetic disorder Albright hereditary osteodystrophy. But these aspects of the disease phenotype are only seen in individuals with mutations on the maternal allele of the gene encoding Gαs, GNAS. This occurs because genomic imprinting causes expression primarily from the maternal allele of GNAS in some tissues. Chen et al. provide evidence that it is differential expression of GNAS in the brain that accounts for the metabolic effects of the disease. The central nervous system regulates energy metabolism and, in particular, the melanocortins function there through Gαs-coupled receptors to control energy expenditure and food intake. The authors observed evidence of imprinting in some areas of the mouse brain known to control metabolism, in particular the paraventricular nucleus of the hypothalamus. Chen et al. generated mice with specific disruption in the CNS of the maternal or paternal allele of the gene encoding Gαs and observed that only animals with the maternal gene affected became obese, apparently as a result of reduced energy expenditure. Animals with the disrupted maternal allele also became insulin resistant and diabetic even before they became obese. Loss of Gαs function in the CNS mimicked some, but not all, of the effects seen with loss of the MC4R melanocortin receptor. In particular, effects of melanocortin on food intake appear to be signaled independently of Gαs. On the other hand, stimulation of energy expenditure by melanocortin was diminished in animals with the mutant female allele. The results enhance understanding of energy homeostasis and should help define effective therapies for metabolic diseases.

M. Chen, J. Wang, K. E. Dickerson, J. Kelleher, T. Xie, D. Gupta, E. W. Lai, K. Pacak, O. Gavrilova, L. S. Weinstein, Central nervous system imprinting of the G protein Gsα and its role in metabolic regulation. Cell Metab. 9, 548–555 (2009). [PubMed]