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Metabolic Diseases Branch (M.C., N.J.W., J.L., L.S.W.) and Diabetes Branch (M.H., K.R.D., M.L.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Lee S. Weinstein, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Building 10, Room 8C101, Bethesda, Maryland 20892-1752. E-mail: leew{at}amb niddk.nih.gov.
The G protein 
-subunit Gs is required for hormone-stimulated cAMP generation. The Gs gene Gnas is a complex gene with multiple imprinted gene products. Mice with heterozygous disruption of the Gnas paternal allele (+/p–) are partially Gs deficient and totally deficient in XLs, a neuroendocrine-specific Gs isoform that is expressed only from the paternal Gnas allele. We previously showed that these mice are hypermetabolic and lean and have increased insulin sensitivity. We now performed hyperinsulinemic-euglycemic clamp studies, which confirmed the markedly increased whole body insulin sensitivity in +/p– mice. +/p– mice had 1.4-, 7- and 3.8-fold increases in insulin-stimulated glucose uptake in muscle and white and brown adipose tissue, respectively, and markedly suppressed endogenous glucose production from the liver. This was associated with increased phosphorylation of insulin receptor and a downstream effector (Akt kinase) in both liver and muscle in response to insulin. Triglycerides cleared more rapidly in +/p– mice after a bolus administered by gavage. This was associated with decreased liver and muscle triglyceride content and increased muscle acyl-CoA oxidase mRNA expression. Resistin and adiponectin were overexpressed in white adipose tissue of +/p– mice, although there was no difference in serum adiponectin levels. The lean phenotype and increased insulin sensitivity observed in +/p– mice is likely a consequence of increased lipid oxidation in muscle and possibly other tissues. Further studies will clarify whether XLs deficiency is responsible for these effects and if so, the mechanism by which XLs deficiency leads to this metabolic phenotype.
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