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

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2005; 102(20):7386-91. DOI: 10.1073/pnas.0408268102
Source: PubMed


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.

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    • "Mice were analyzed at P14. Error bars represent SD (n = 8). mouse lines (Chen et al., 2005). In order to study differential requirements of G proteins, we analyzed G protein KO mice for the expression of A-P targeting (e.g., Nrp1) and glomerular segregation molecules (e.g., Kirrel2). "
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    Cell 09/2013; 154(6):1314-25. DOI:10.1016/j.cell.2013.08.033 · 32.24 Impact Factor
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    • "There is also no evidence in the present study or from Eaton et al. (2012) that insertion of the polyA cassette itself reduces the level of Gnas expression. Furthermore, Ex1A-T/? mice do not show the increased adiposity and decreased metabolic rate that is characteristic of mutants with reduced Gnas (Chen et al. 2005; Kelly et al. 2009; Xie et al. 2008). Analysis of other Gnas cluster transcripts confirmed that Nesp was the only transcript in the Gnas cluster that was altered in the Ex1A-T/? "
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    ABSTRACT: Genes subjected to genomic imprinting are often associated with prenatal and postnatal growth. Furthermore, it has been observed that maternally silenced/paternally expressed genes tend to favour offspring growth, whilst paternally silenced/maternally expressed genes will restrict growth. One imprinted cluster in which this has been shown to hold true is the Gnas cluster; of the three proteins expressed from this cluster, two, Gsα and XLαs, have been found to affect postnatal growth in a number of different mouse models. The remaining protein in this cluster, NESP55, has not yet been shown to be involved in growth. We previously described a new mutation, Ex1A-T, which upon paternal transmission resulted in postnatal growth retardation due to loss of imprinting of Gsα and loss of expression of the paternally expressed XLαs. Here we describe maternal inheritance of Ex1A-T which gives rise to a small but highly significant overgrowth phenotype which we attribute to reduction of maternally expressed NESP55.
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    • "These phenotypes include neonatal subcutaneous oedema associated with increased mortality and, in adulthood, resistance to several hormones whose receptors signal via stimulation of cAMP formation (e.g. parathyroid hormone in proximal renal tubules, thyroid stimulating hormone in the thyroid gland) [25], [40], [41]. Mutation of Gnas on the maternal allele also causes severe obesity with reduced energy expenditure and type 2 diabetes mellitus-like symptoms (hyperglycemia, glucose intolerance, hyperinsulinemia and insulin resistance) [20], [41], [42]. "
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