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

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 alpha-subunit (G(s)alpha), the G protein required for receptor-stimulated cAMP production; extralarge G(s)alpha (XL alpha s), a paternally expressed G(s alpha) isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G(s)alpha undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2(m-/+)) or paternal (E2(+/p-)) allele results in opposite effects on energy metabolism. E2(m-/+) mice are obese and hypometabolic, whereas E2(+/p-) mice are lean and hypermetabolic. We now studied the effects of G(s)alpha deficiency without disrupting other Gnas gene products by deleting G(s)alpha exon 1 (El). 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 XL alpha s deficiency, whereas loss of paternal-specific G(s)alpha 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 E2(m-/+) mice, E1(m-/+) mice had s.c. edema at birth, presumably due to loss of maternal G(s)alpha expression. However, E1(m-/+) mice differed from E2(m-/+) mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1(m-/+) mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1(+/p-) mice. Differences between E1(m-/+) and E1(+/p-) mice presumably result from differential effects on G(s)alpha expression in tissues where G(s)alpha is normally imprinted.