The Role of GNAS and Other Imprinted Genes in the Development of Obesity

Genomic imprinting is an epigenetic phenomenon affecting a small number of genes which leads to differential expression from the two parental alleles. Imprinted genes are known to regulate fetal growth and a ‘kinship’ or ‘parental conflict’ model predicts that paternally- and maternally-expressed imprinted genes promote and inhibit fetal growth, respectively. In this review we examine the role of imprinted genes in postnatal growth and metabolism, with an emphasis on the GNAS/Gnas locus. GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G protein α-subunit Gsα which is expressed primarily from the maternal allele in some tissues and the Gsα isoform XLαs which is expressed only from the paternal allele. Maternal, but not paternal, Gsα mutations lead to obesity in Albright hereditary osteodystrophy. Mouse studies show that this phenomenon is due to Gsα imprinting in the central nervous system leading to a specific defect in the ability of central melanocortins to stimulate sympathetic nervous system activity and energy expenditure. In contrast mutation of paternally-expressed XLαs leads to opposite metabolic effects in mice. While these findings conform to the ‘kinship’ model, the effects of other imprinted genes on body weight regulation do not conform to this model.