Exon XL has been disrupted in mice through introduction of a small deletion into the beginning part of both XLαs and ALEX ORF; this disruption appears to preserve the imprinted expression of other Gnas transcripts [67]. The mice with paternal inheritance of the disrupted XLαs allele (Gnasxl knockout mice) lack XLαs expression, consistent with the exclusive paternal expression of the XLαs transcript. The Gnasxl knockout pups show defective suckling, hypoglycemia, growth retardation, and early postnatal mortality. Despite having hypoglycemia, the Gnasxl knockout mice show reduced glucagon levels and inappropriately normal serum catecholamine and cortisol levels, suggesting a possible impairment of the physiological responses to hypoglycemia. When crossed into the CD1 background, about 20% of the Gnasxl knockout animals survive with an apparently normal life-span. However, these mice display increased glucose tolerance and insulin sensitivity, as well as a hypermetabolic state associated with reduced adiposity and hypolipidemia [67]. In addition, circulating levels of norepinephrine is elevated in these animals, indicating increased sympathetic nervous system activity, which explains, at least in part, the defects in the energy metabolism [76]. On the other
