Growing Fat with Mom's Help

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Science  26 Jun 2009:
Vol. 324, Issue 5935, pp. 1619
DOI: 10.1126/science.324_1619b

A mutation in the α subunit of the guanine nucleotide–binding protein Gs, which transduces signals from various hormone receptors, causes obesity and insulin resistance in the human disorder Albright hereditary osteodystrophy. These disease manifestations occur in individuals with mutations in the maternal allele of the gene encoding Gαs, GNAS, because genomic imprinting causes expression primarily from the maternal allele of GNAS in some tissues. Chen et al. provide evidence that the differential expression of GNAS in the brain (the paraventricular nucleus of the hypothalamus) accounts for the metabolic effects of the disease. They observed that mice with a disrupted maternal Gαs allele became obese as a result of reduced energy expenditure. These animals also became insulin-resistant and diabetic even before they became obese. Loss of Gαs function mimicked some of the effects seen with loss of the MC4R melanocortin receptor; melanocortins function through Gαs-coupled receptors to control energy expenditure and food intake. Specifically, effects of melanocortin on food intake operated independently of Gαs. On the other hand, the stimulation of energy expenditure by melanocortin was diminished in animals carrying the mutant maternal allele.

Cell Metab. 9, 548 (2009).

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