新Wnt信号通路调节子在白色脂肪棕色化及肥胖发生中作用

White-to-brown adipocyte switch was proposed to be an effective way to combat overweight and obesity; however, few ideal browning genes were identified until now. Our previously published data demonstrated that LGR4, as a novel Wnt co-receptor, could regulate browning programme in mice and its gain-of-function variant predisposed obesity in humans (Nat Cell Biol-2013). Our recently unpublished data shown that RSPO1, as one endogenous ligand of LGR4, could also regulate browning process both in vivo and in vitro, potentially by LGR4-β-Catenin pathway. RSPOs, LGR4 and ZNRF3/RNF43, which constitute a novel Module of canonical Wnt signaling, were proposed to regulate white-to-brown conversion together. We propose to illustrate the role and moleclular mechanism of each member gene in the browning and the development of obesity by genetic modified mice models and biological studies. Meanwhile, we will assess the rare functinonal variants of these module genes by deep sequencing and functional analysis.

白色脂肪棕色化是阻遏超重与肥胖的潜力手段，但目前仍缺乏明确的干预靶点。我们前期工作已经揭示了Wnt通路新调节基因LGR4在小鼠白色脂肪棕色化与人类肥胖发生中的作用（Nat Cell Biol-2013）；我们最近的系列结果表明，LGR4的内源性配体RSPO1通过LGR4调控体内外白色脂肪棕色化过程，经典Wnt信号通路核心分子β-Catenin亦发挥关键作用。RSPOs、LGR4及其降解蛋白ZNRF3/RNF43共同组成了经典Wnt信号通路的“新调节子（Module）”，我们拟通过构建多种基因修饰小鼠模型，全面阐述该“调节子”成员基因在白色脂肪棕色化及肥胖发生中的作用；并借助已完成的规模青少年重度肥胖全外显子测序，重点评估该通路突变与临床肥胖发生的关系。以期提出白色脂肪棕色化领域新观点、解释肥胖症新病因。

研究WAT棕色化机制近年来是肥胖病因分析和治疗探索领域的热点话题。本项目利用RSPO1-LGR4-β-catenin信号通路各节点基因修饰小鼠模型，通过深入代谢表型分析和细胞、分子机理研究，全面阐述该信号通路在白色脂肪棕色化及肥胖发生中的作用。重要的是，借助项目前期建立的中国青少年极端肥胖队列，发现RSPO1-LGR4-ZNRF3-β-catenin多个WNT通路新节点基因的功能性突变直接参与白色脂肪棕色化与肥胖发生过程。并且，通过构建脂肪细胞特异性或者人源化点突变小鼠模型，深入探讨其调节白色脂肪棕色化的分子机制，为肥胖治疗提供新思路。