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Severe Obesity and Insulin Resistance due to Deletion of the Maternal G_s Allele Is Reversed by Paternal Deletion of the G_s Imprint Control Region

Metabolic Diseases Branch (T.X., M.C., J.L., L.S.W.) and Mouse Metabolism Core Laboratory (O.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Reproductive and Adult Endocrinology Program (E.W.L.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Lee S. Weinstein, M.D., 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 G_s mediates receptor-stimulated cAMP production and is imprinted with reduced expression from the paternal allele in specific tissues. Disruption of the G_s maternal (but not paternal) allele leads to severe obesity, hypertriglyceridemia, and insulin resistance in mice and obesity in patients with Albright hereditary osteodystrophy. Paternal deletion of a G_s imprint control region (1A) leads to loss of tissue-specific G_s imprinting. To determine whether the metabolic abnormalities resulting from disruption of the G_s maternal allele could be reversed by loss of paternal G_s imprinting, females with a heterozygous G_s exon 1 deletion were mated to males with heterozygous deletion of the imprint control region (1A) to generate mice with maternal G_s deletion (E1^m–), paternal 1A deletion (1A^p–), double mutants (E1^m–:1A^p–), and wild type. E1^m– mice developed obesity, glucose intolerance, insulin resistance, and hypertriglyceridemia, which were all normalized by the paternal 1A deletion in E1^m–:1A^p– mice. Obesity in E1^m– was associated with reduced energy expenditure and sympathetic nerve activity, and these were also normalized in E1^m–:1A^p– mice. 1A^p– mice had reduced body weight associated with proportional decreases in fat and lean mass as well as increased activity levels. The metabolic phenotype resulting from maternal G_s deletion is rescued by a genetic lesion that leads to loss of tissue-specific G_s imprinting, consistent with this phenotype being a direct consequence of G_s imprinting in one or more specific tissues.