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

M Chen, O Gavrilova, J Liu, T Xie… - Proceedings of the …, 2005 - National Acad Sciences
M Chen, O Gavrilova, J Liu, T Xie, C Deng, AT Nguyen, LM Nackers, J Lorenzo, L Shen…
Proceedings of the National Academy of Sciences, 2005National Acad Sciences
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 …
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.
National Acad Sciences