title: 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 alpha-subunit (G(s)alpha), the G protein required for receptor-stimulated cAMP production; extralarge G(s)alpha (XLalphas), 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 (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 G(s)alpha deficiency without disrupting other Gnas gene products by deleting G(s)alpha 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 XLalphas 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 E2m-/+ mice, E1m-/+ mice had s.c. edema at birth, presumably due to loss of maternal G(s)alpha 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 G(s)alpha expression in tissues where G(s)alpha is normally imprinted.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Annie T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nackers
authors.forename: Javier
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Laura
authors.initials: L
authors.lastname: Shen
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D015152:Blotting, Northern; D001823:Body Composition; D002864:Chromogranins; D017931:DNA Primers; D004734:Energy Metabolism / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D005822:Genetic Vectors; D018392:Genomic Imprinting / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002864:Chromogranins; D017931:DNA Primers; D020033:Protein Isoforms; D014280:Triglycerides; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs; D005947:Glucose