Role of Gsα in Central Regulation of Energy and Glucose Metabolism

GNAS is a complex imprinted locus with multiple oppositely imprinted gene products, including the G protein alpha-subunit G(s)alpha that is expressed primarily from the maternal allele in some tissues and the G(s)alpha isoform XL alpha s that is expressed only from the paternal allele. Maternal G(s)alpha mutations in mice and in patients with Albright hereditary osteodystrophy lead to obesity, insulin resistance, and hyperlipidemia. Studies in mice show that these effects are primarily due to G(s)alpha imprinting in the central nervous system and that G(s)alpha deficiency in one or more regions of the central nervous system lead to reduced sympathetic nervous system and energy expenditure without affecting food intake. Loss of G(s)alpha in the central nervous system appears to lead to these effects primarily through impairment of melanocortin signaling. Loss of XL alpha s in mice leads to opposite effects on energy and glucose metabolism.