SH2-B Regulation of Hypothalamic AgRP/NPY Neurons

描述（由申请人提供）：瘦素通过其对中枢神经系统的生物作用来抑制食物摄入。SH2-B是一种JAK2结合蛋白，在下丘脑的瘦素敏感神经元中表达，并在培养细胞中促进瘦素信号传导。SH2-B缺陷小鼠出现贪食、瘦素抵抗和肥胖，证实SH2-B是体内瘦素作用和能量平衡的关键介质。这一建议将解决SH2-B在AgRP神经元中的作用，AgRP神经元是下丘脑中瘦素敏感神经元的一个群体，与食物摄入的控制有关。条件功能丧失方法（Cre/LoxP）将用于验证SH2-B主要通过调节下丘脑弓状核AgRP神经元中瘦素敏感性来调节能量平衡的中心假设。将确定SH2-B直接调节AgRP神经元中瘦素信号传导的程度（目的1），并将讨论AgRP神经元中SH2-B对能量平衡和瘦素敏感性的内在调节的相对贡献（目的2）。这些研究将对SH2-B促进瘦素敏感性和参与能量稳态中枢调节的机制提供相当深入的见解。

DESCRIPTION (provided by applicant): Leptin suppresses food intake via its biological actions on the central nervous system. SH2-B, a JAK2 binding protein, is expressed in leptin-sensitive neurons within the hypothalamus, and promotes leptin signaling in cultured cells. SH2-B deficient mice develop hyperphagia, leptin resistance, and obesity, confirming that SH2-B is a key mediator of leptin action and energy balance in vivo. This proposal will address the role of SH2-B in AgRP neurons, one population of leptin sensitive neurons in the hypothalamus implicated in the control of food intake. A conditional loss-of-function approach (Cre/LoxP) will be used to test the central hypothesis that SH2-B regulates energy balance predominantly by regulating leptin sensitivity in AgRP neurons within the arcuate nucleus of the hypothalamus. The extent to which SH2-B directly regulates leptin signaling in AgRP neurons will be determined (aim 1), and the relative contribution of SH2-B in AgRP neurons to the intrinsic regulation of energy balance and leptin sensitivity (aim 2) will be addressed. These studies will provide considerable insight into the mechanisms by which SH2-B promotes leptin sensitivity and contributes to the central regulation of energy homeostasis.