Abstract
The complex imprinted Gnas locus encodes several gene products including G(s)alpha, the ubiquitously expressed G protein alpha-subunit required for receptor-stimulated cAMP generation, and the neuroendocrine-specific G(s)alpha isoform XLalphas. XLalphas is only expressed from the paternal allele, whereas G(s)alpha is biallelically expressed in most tissues. XLalphas knock-out mice (Gnasxl(m+/p-)) have poor suckling and perinatal lethality, implicating XLalphas as critical for postnatal feeding. We have now examined the metabolic phenotype of adult Gnasxl(m+/p-) mice. Gnasxl(m+/p-) mice had reduced fat mass and lipid accumulation in adipose tissue, with increased food intake and metabolic rates. Gene expression profiling was consistent with increased lipid metabolism in adipose tissue. These changes likely result from increased sympathetic nervous system activity rather than adipose cell-autonomous effects, as we found that XLalphas is not normally expressed in adult adipose tissue, and Gnasxl(m+/p-) mice had increased urinary norepinephrine levels but not increased metabolic responsiveness to a beta3-adrenergic agonist. Gnasxl(m+/p-) mice were hypolipidemic and had increased glucose tolerance and insulin sensitivity. The similar metabolic profile observed in some prior paternal Gnas knock-out models results from XLalphas deficiency (or deficiency of the related alternative truncated protein XLN1). XLalphas (or XLN1) is a negative regulator of sympathetic nervous system activity in mice.
Highlights
The complex imprinted Gnas locus encodes several gene products including Gs␣, the ubiquitously expressed G protein ␣-subunit required for receptor-stimulated cAMP generation, and the neuroendocrine-specific Gs␣ isoform XL␣s
In this study we show that XL␣s deficiency leads to reduced adiposity and increased metabolic rate and insulin sensitivity
Multiple genes involved in lipolysis and fatty acid oxidation and thermogenesis (PPAR␥ coactivator-1, uncoupling protein 1, acyl-CoA oxidase, thyroid hormone receptor ␣, nuclear respiratory factor 1, and mitochondrial transcription factor A), most of which are known to be stimulated by -adrenergic/Gs␣/cAMP-signaling pathways [26, 30], are up-regulated in white adipose tissue (WAT), and to a lesser extent in BAT, of Gnasxl mϩ/pϪ mice
Summary
Animals—Gnasxl mϩ/pϪ mice [7] were repeatedly mated with CD1 wild-type mice (Charles River, Wilmington, MA) for Ͼ5 generations and were maintained on a standard pellet diet (NIH-07, 5% fat by weight) and 12 h:12 h light/dark cycle. Blood glucose levels in tail vein bleeds were measured using a Glucometer Elite (Bayer, Elkhart, IN) immediately before and at the indicated times after injection. By 3 weeks of age, from frozen tissues using TRIzol (Invitrogen) or an Mini RNeasy Gnasxl mϩ/pϪ mice had a survival rate that was ϳ27% that kit (Qiagen, Germantown, MD) and treated with DNase (DNA- expected by Mendelian inheritance (8 of 59 total offspring), and JULY 14, 2006 VOLUME 281 NUMBER 28. The relative weight of testes and lungs were slightly, significantly increased in Gnasxl mϩ/pϪ mice as compared with controls Histology of both BAT and WAT from Gnasxl mϩ/pϪ mice showed reduced lipid accumulation and size of adipocytes (Fig. 2E).
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