SH2-B Regulation of Hypothalamic AgRP/NPY Neurons

描述(申请人提供)：瘦素通过其对中枢神经系统的生物学作用抑制食物摄取。Sh2-B是一种JAK2结合蛋白，在下丘脑内的瘦素敏感神经元中表达，并促进培养细胞中的瘦素信号转导。Sh2-B基因缺陷小鼠出现吞噬功能亢进、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。这项建议将讨论SH2-B在AgRP神经元中的作用，AgRP神经元是下丘脑中一种瘦素敏感神经元，与控制食物摄入量有关。一个条件功能丧失方法(CRE/loxP)将被用来检验SH2-B主要通过调节下丘脑弓状核内AgRP神经元的瘦素敏感性来调节能量平衡的中心假设。SH2-B直接调节AgRP神经元中瘦素信号的程度将被确定(目标1)，并将解决在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(目标2)。这些研究将为SH2-B促进瘦素敏感性的机制提供相当大的洞察力，并有助于能量平衡的中央调节。

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.