The alternative stimulatory G protein α-subunit XLαs is a critical regulator of energy and glucose metabolism and sympathetic nerve activity in adult mice

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 XL alpha s. XL alpha s is only expressed from the paternal allele, whereas G(s)alpha is biallelically expressed in most tissues. XL alpha s knock-out mice (Gnasxl (m+/p-)) have poor suckling and perinatal lethality, implicating XL alpha s 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 XL alpha s 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 beta 3-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 XL alpha s deficiency (or deficiency of the related alternative truncated protein XLN1). XL alpha s ( or XLN1) is a negative regulator of sympathetic nervous system activity in mice.