Severe obesity and insulin resistance due to deletion of the maternal Gsalpha allele is reversed by paternal deletion of the Gsalpha imprint control region.
The G protein alpha-subunit G(s)alpha mediates receptor-stimulated cAMP production and is imprinted with reduced expression from the paternal allele in specific tissues. Disruption of the G(s)alpha 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)alpha imprint control region (1A) leads to loss of tissue-specific G(s)alpha imprinting. To determine whether the metabolic abnormalities resulting from disruption of the G(s)alpha maternal allele could be reversed by loss of paternal G(s)alpha imprinting, females with a heterozygous G(s)alpha exon 1 deletion were mated to males with heterozygous deletion of the imprint control region (1A) to generate mice with maternal G(s)alpha 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)alpha deletion is rescued by a genetic lesion that leads to loss of tissue-specific G(s)alpha imprinting, consistent with this phenotype being a direct consequence of G(s)alpha imprinting in one or more specific tissues.
Xie
Tao
T
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Building 10, Room 8C101, Bethesda, Maryland 20892-1752, USA.
Chen
Min
M
Gavrilova
Oksana
O
Lai
Edwin W
EW
Liu
Jie
J
Weinstein
Lee S
LS
D000483:Alleles; D000818:Animals; D004487:Edema / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005091:Exons; D005220:Fathers; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D017353:Gene Deletion; D005804:Genes, Lethal; D018392:Genomic Imprinting / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D040582:Inheritance Patterns; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009035:Mothers; D009767:Obesity, Morbid / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012871:Skin Diseases / Q000235:genetics
D019205:GTP-Binding Protein alpha Subunits, Gs; D005947:Glucose