Alternative Gnas gene products have opposite effects on glucose and lipid metabolism

Abstract Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein α-subunit (Gsα), the G protein required for receptor-stimulated cAMP production; extralarge Gsα (XLαs), a paternally expressed Gsα isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. Gsα undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2m-/+) or paternal (E2+/p-) allele results in opposite effects on energy metabolism. E2m-/+ mice are obese and hypometabolic, whereas E2+/p- mice are lean and hypermetabolic. We now studied the effects of Gsα deficiency without disrupting other Gnas gene products by deleting Gsα exon 1 (E1). E1+/p- mice lacked the E2+/p- phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2+/p- phenotype appears to result from XLαs deficiency, whereas loss of paternal-specific Gsα expression in E1+/p- mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2m-/+ mice, E1m-/+ mice had s.c. edema at birth, presumably due to loss of maternal Gsα expression. However, E1m-/+ mice differed from E2m-/+ mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1m-/+ mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1+/p- mice. Differences between E1m-/+ and E1+/p- mice presumably result from differential effects on Gsα expression in tissues where Gsα is normally imprinted. G protein genomic imprinting pseudohypoparathyroidism