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

The G protein α-subunit Gsα mediates receptor-stimulated cAMP production and is imprinted with reduced expression from the paternal allele in specific tissues. Disruption of the Gsα 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 Gsα imprint control region (1A) leads to loss of tissue-specific Gsα imprinting. To determine whether the metabolic abnormalities resulting from disruption of the Gsα maternal allele could be reversed by loss of paternal Gsα imprinting, females with a heterozygous Gsα exon 1 deletion were mated to males with heterozygous deletion of the imprint control region (1A) to generate mice with maternal Gsα deletion (E1m−), paternal 1A deletion (1Ap−), double mutants (E1m−:1Ap−), and wild type. E1m− mice developed obesity, glucose intolerance, insulin resistance, and hypertriglyceridemia, which were all normalized by the paternal 1A delet...