Chen Min, Wang Jie, Dickerson Kathryn E, Kelleher James, Xie Tao, Gupta Divakar, Lai Edwin W, Pacak Karel, Gavrilova Oksana, Weinstein Lee S
Signal Transduction Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Metab. 2009 Jun;9(6):548-55. doi: 10.1016/j.cmet.2009.05.004.
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.
在奥尔布赖特遗传性骨营养不良症中，这是一种与介导受体刺激的环磷酸腺苷（cAMP）生成的G蛋白G(s)α杂合突变相关的单基因肥胖症，肥胖仅在突变位于母本等位基因时才会发生。同样，具有母本（而非父本）种系G(s)α突变的小鼠会出现肥胖、胰岛素抵抗和糖尿病。这些源自亲本的效应是由于G(s)α印记，在某些组织中母本等位基因有优先表达。由于G(s)α在全身广泛表达，参与这种代谢印记效应的组织尚不清楚。通过使用脑特异性G(s)α基因敲除小鼠，我们表明中枢神经系统内的G(s)α印记是这些效应的基础，并且G(s)α在下丘脑室旁核中存在印记。母本G(s)α突变损害了黑皮质素对能量消耗的刺激，但不影响黑皮质素对食物摄入的作用，这表明黑皮质素可能通过G(s)α依赖和非依赖途径调节中枢神经系统中的能量平衡。
