Central Nervous System Imprinting of the G Protein Gsα and Its Role in Metabolic Regulation |
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| Authors: | Min Chen Jie Wang Kathryn E. Dickerson James Kelleher Tao Xie Divakar Gupta Edwin W. Lai Karel Pacak Oksana Gavrilova Lee S. Weinstein |
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| Affiliation: | 1. Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;2. Mouse Metabolism Core Laboratory, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;3. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA |
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| Abstract: | In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of Gsα, 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 Gsα mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to Gsα imprinting, with preferential expression from the maternal allele in some tissues. As Gsα is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific Gsα knockout mice, we show that Gsα imprinting within the central nervous system underlies these effects and that Gsα is imprinted in the paraventricular nucleus of the hypothalamus. Maternal Gsα 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 Gsα-dependent and -independent pathways. |
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| Keywords: | HUMDISEASE MOLNEURO |
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