脂肪分泌的瘦素（leptin）如发生突变，将导致严重肥胖、脂代谢紊乱和糖尿病。但在大部份肥胖人群中，瘦素水平和体脂含量基本成正比，由此产生“瘦素抵抗”而导致肥胖。既往研究认为，瘦素诱发的下丘脑区域中SOCS-3以及PTP-1B 的表达增加是瘦素抵抗的原因之一。 我们近期发表的研究成果首次揭示了一种新的机制：炎症因子CRP在肥胖人群中上升，通过与瘦素的结合，阻止瘦素与其受体结合，抑制其功能，并抑制瘦素穿过血脑屏障进入中枢神经系统。前期结果显示，通过敲除CRP基因表达，大鼠的体脂含量与能量摄取降低，胆固醇水平显著下降。我们将利用CRP 敲除大鼠、人源CRP转基因小鼠等模型，系统性地揭示CRP导致瘦素抵抗、肥胖和糖脂代谢紊乱的分子机制，并揭示CRP对胆固醇代谢通路的调控机制。我们将设计多肽药物阻断CRP:Leptin 的相互作用，缓解瘦素抵抗，为减肥降脂药物提供新的多肽药物靶点以及相关理论依据。

Genetic mutation of leptin gene, whose protein is almost exclusively produced and secreted from adipocytes, is known to cause morbid obesity, severe dyslipidemia, diabetes, and other metabolic diseases. However, in majority of obese population, leptin is abundant in the blood and its level is generally proportional to the level of adiposity, a phenomenon that gave rise to the concept of “leptin resistance”. Already, one of the mechanisms described in the literatures entails leptin-induced overexpression of SOCS-3 and PTP-1B in the hypothalamus, which in turn can diminish leptin signaling and weight reducing actions. A series of our recent studies revealed a completely novel mechanism: the C-reactive protein (CRP) produced and secreted from the liver, binds to leptin, which prevents the binding of leptin to its receptors, suppresses leptin’s functions, and prevents leptin’s entry into the CNS across the blood brain barrier (BBB). Recently, we generated the CRP-knockout rat model using TALENT technology. Preliminary studies found that, through eliminating the expression of rat CRP, the adiposity of rat and energy-intake significantly deceased, and the blood cholesterol levels dropped sharply. This proposed study intends to systematically study and validate the novel mechanisms underlying CRP-induced leptin resistance，dyslipidemia, and hyperglycemia. Meanwhile, we will investigate the mechanisms by which CRP impacts cholesterol metabolism. In addition, we will screen and test the synthetic peptides that will alleviate the interaction of CRP:leptin, reduce CRP-induced leptin resistance, increase leptin’s entry into CNS. Such study will potentially reveal the new generation of peptide drugs targeting the CRP:leptin interaction.