The Alternative Stimulatory G Protein α-Subunit XLαs Is a Critical Regulator of Energy and Glucose Metabolism and Sympathetic Nerve Activity in Adult Mice

Abstract The complex imprinted Gnas locus encodes several gene products including Gsα, the ubiquitously expressed G protein α-subunit required for receptor-stimulated cAMP generation, and the neuroendocrine-specific Gsα isoform XLαs. XLαs is only expressed from the paternal allele, whereas Gsα is biallelically expressed in most tissues. XLαs knock-out mice (Gnasxlm+/p–) have poor suckling and perinatal lethality, implicating XLαs as critical for postnatal feeding. We have now examined the metabolic phenotype of adult Gnasxlm+/p– mice. Gnasxlm+/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 XLαs is not normally expressed in adult adipose tissue, and Gnasxlm+/p– mice had increased urinary norepinephrine levels but not increased metabolic responsiveness to a β3-adrenergic agonist. Gnasxlm+/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 XLαs deficiency (or deficiency of the related alternative truncated protein XLN1). XLαs (or XLN1) is a negative regulator of sympathetic nervous system activity in mice.