经典Wnt信号通路核心分子在白色脂肪棕色化调控中的作用与机制

Several genetic evidence has demonstrated that the mutations or common variants in the genes of Wnt pathway are tightly linked to adiposity and cardiometabolic disorders in humans. Canonical Wnt pathway further controls the differentiation of white adipocytes. However, the roles of β-Catenin, the core factor in the pathway, in the browning programme of white adipocytes remain largely unknown. My group focuses on the browning and obesity for more than 10 years, and reported that a novel Wnt module LGR4 controlled the white-to-brown adipocyte switch and the development of obesity. Herein, we found the rare CTNNB1 mutaitons were enriched in obese populations, and further created a time and browning tissue-specific β-Catenin knockout mice using a Tamoxifen-inducible Ucp1-cre knockin mouse model. We found that an enhanced browning process was present in the inguinal white adipose tissues, characterized by increased Ucp1 protein expression, when β-Catenin was ablated. Further ex vivo and in vitro evidence indicated that TCF7L2 and PPARγ2 were involved into the browning programme, but the exact molecular mechanism needed further illustration. In this proposal we aim to provide more detailed information about clinical features of the mutation carriers, the mechanism using genetic knockout mouse model and a potential obesity intervention with pharmacological blockade. The potential conclusion would be of importance to the fate determination of beige adipocytes, etiology of obesity and clinical intervention strategy.

大量遗传学证据表明Wnt通路突变与人类肥胖密切关联；基础研究表明Wnt通路在白色脂肪分化中扮演重要角色。然而，作为经典Wnt通路核心分子β-Catenin在棕色脂肪及白色脂肪棕色化中的作用尚不清楚。申请人长期聚焦肥胖人群遗传分析、Wnt通路新分子LGR4调节棕色化方向，发现β-Catenin可作为LGR4新下游通路参与棕色化过程。前期工作基础包括：发现人类β-Catenin突变富集于肥胖人群；首次建立可诱导性Ucp1-cre Knockin工具小鼠实现β-Catenin时空特异性敲除，发现其在冷冻刺激下棕色化能力明显增强；离体和体外细胞试验进一步验证此结果；并发现TCF7L2与PPARγ可能参与上述过程。拟继续评估突变携带者家系的肥胖特征及代谢指标，在体内外试验中验证β-Catenin在白色脂肪棕色化及能量平衡中的作用，阐明其具体调控机制，探讨拮抗该通路实现减肥干预可能。

营养过剩会导致肥胖和慢性炎症，并伴有白色脂肪组织 (WAT) 的扩张。然而，控制脂肪含量和肥胖的遗传因素在很大程度上仍未确定。我们在年轻肥胖受试者中应用了全外显子组测序，并在 CTNNB1/β-catenin 中发现了与肥胖风险增加相关的罕见功能获得性突变。成熟脂肪细胞中 β-catenin特异性敲除减弱了高脂肪饮食诱导的肥胖，并减少了 sWAT 质量扩张，同时 Pdgfra + 前脂肪细胞和成熟脂肪细胞增殖较少。从机制上讲，β-catenin蛋白通过成熟脂肪细胞中的 β-catenin-TCF复合物调节血清淀粉样蛋白 3 (Saa3) 的转录，Saa3 是一种脂肪细胞衍生的趋化因子，Saa3 激活巨噬细胞分泌多种因子，包括 Pdgf-aa，它进一步促进了前脂肪细胞的增殖，表明 β-cateninn/Saa3/巨噬细胞可能介导成”熟脂肪细胞-前脂肪细胞“对话和 sWAT 中的脂肪扩张。确定β-catenin是脂肪扩张和人类肥胖的关键调节因子，为开发靶向 Wnt/β-catenin通路的药物以对抗肥胖提供了基础。