近年来,下丘脑作为调节机体代谢和能量平衡的枢纽在肥胖和胰岛素抵抗中的作用备受关注。已有研究显示下丘脑能够感知营养素、细胞因子和激素信号的变化对机体脂糖代谢进行调节。SFRP5,作为一个与代谢相关的细胞因子，其在机体外周组织的作用已有报道。然而，其信号在体内“脑-肝”之间转导对代谢的调节机制，目前并不清楚。本课题的前期研究发现：下丘脑SFRP5表达增加的高脂喂养大鼠，胰岛素敏感性明显增强。进一步在细胞实验中发现过表达SFRP5能激活AKT/PI3K信号系统。因此本研究拟从中枢和外周组织器官两个层面将中枢第三脑室微量灌注系统和扩展胰岛素钳夹技术相结合,并利用3-[3H]葡萄糖、2-脱氧-3H葡萄糖和C14乳酸盐三种示踪技术及分子生物学方法，分别探讨下丘脑SFRP5信号变化对外周组织脂-糖代谢动力学的影响。本课题将从体内代谢组学的角度，全面解读SFRP5及“脑-肝”轴对脂-糖代谢调节的意义。

The hypothalamus, as a center of Metabolism and energy homeostasis, has been receiving increasing attention due largely to its role in obesity and insulin resistance (IR). It has been demonstrated that the hypothalamus can sense cytokine, hormones and nutrients to regulate lipid and glucose homeostasis. Although the metabolic effects of SFRP5 have been reported, to date, it is unknown whether this peptide signals are mediated through a brain-liver neuronal network to control glucose and lipid homeostasis in vivo. Previous research has found that the increase in hypothalamic SFRP5 expression on high fat diet accompany with ameliorate insulin sensitivity.Overexpression SFRP5 can activate AKT/PI3K signaling system in cell experiment. In this study, the effects of SFRP5 on glucose and lipid kinetics will be assessed by association intracerebroventricular infusions with euglycemic-hyperinsulinemic clamp studies based on three tracer-dilution methodologies as well as molecular biology methods. In addition, the effects of central SFRP5 on glucose and lipid kinetics will be also assessed by SFRP5 Neutralizing antibody. Finally, the underlying brain-liver neuronal network and molecule mechanisms of SFRP5 signaling will be further revealed. These data will highlight a previously unappreciated role of central SFRP5 signaling in regulation of glucose and lipid homeostasis and insulin sensitivity.