SH2-B Regulation of Hypothalamic AgRP/NPY Neurons

性状（由申请方提供）：瘦素通过其对中枢神经系统的生物学作用抑制食物摄入。SH 2-B是一种JAK 2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传导。SH 2-B缺陷型小鼠出现摄食过多、瘦素抵抗和肥胖，证实了SH 2-B是体内瘦素作用和能量平衡的关键介质。该提议将阐述SH 2-B在AgRP神经元中的作用，AgRP神经元是下丘脑中涉及食物摄入控制的瘦素敏感神经元的一个群体。将使用条件性功能丧失方法（Cre/LoxP）来检验中心假设，即SH 2-B主要通过调节下丘脑弓状核内AgRP神经元中的瘦素敏感性来调节能量平衡。将确定SH 2-B直接调节AgRP神经元中的瘦素信号传导的程度（目的1），并将解决AgRP神经元中的SH 2-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）。这些研究将为SH 2-B促进瘦素敏感性并有助于能量稳态的中枢调节的机制提供相当多的见解。

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.