Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.
In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of G(s)alpha, the G protein that mediates receptor-stimulated cAMP generation, obesity develops only when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline G(s)alpha mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to G(s)alpha imprinting, with preferential expression from the maternal allele in some tissues. As G(s)alpha is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific G(s)alpha knockout mice, we show that G(s)alpha imprinting within the central nervous system underlies these effects and that G(s)alpha is imprinted in the paraventricular nucleus of the hypothalamus. Maternal G(s)alpha mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both G(s)alpha-dependent and -independent pathways.
Chen
Min
M
Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. minc@intra.niddk.nih.gov
Wang
Jie
J
Dickerson
Kathryn E
KE
Kelleher
James
J
Xie
Tao
T
Gupta
Divakar
D
Lai
Edwin W
EW
Pacak
Karel
K
Gavrilova
Oksana
O
Weinstein
Lee S
LS
D000483:Alleles; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018392:Genomic Imprinting; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D053486:Melanocortins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009765:Obesity / Q000235:genetics
D053486:Melanocortins; D019205:GTP-Binding Protein alpha Subunits, Gs; D005947:Glucose