Alternative Gnas Gene Products Have Opposite Effects on Glucose and Lipid Metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 20; pp. 7386 - 7391
• Main Authors: Chen, Min, Gavrilova, Oksana, Liu, Jie, Xie, Tao, Deng, Chuxia, Nguyen, Annie T., Nackers, Lisa M., Lorenzo, Javier, Shen, Laura, Weinstein, Lee S., Birnbaumer, Lutz
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17-05-2005; National Acad Sciences
• Subjects: Alleles; Alternative Splicing - genetics; Analysis of Variance; Animals; Biological Sciences; Blood Glucose; Blotting, Northern; Body Composition; Chromogranins; DNA Primers; Edema; Effects; Energy Metabolism - genetics; Exons; Genes; Genetic mutation; Genetic Vectors; Genomic Imprinting - genetics; Glucose; Glucose - metabolism; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Insulin; Insulin resistance; Insulin Resistance - genetics; Lipid Metabolism; Lipids; Metabolism; Mice; Mice, Knockout; Mutation - genetics; Obesity; Phenotype; Phenotypes; Protein Isoforms - genetics; Protein Isoforms - metabolism; Radioimmunoassay; Triglycerides - blood
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408268102

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.