Wnt信号通路调节分子R-spondin1调节白色脂肪棕色化及能量代谢的作用及机制研究

Recent studies demonstrate that white adipocyte can be switched to brown adipocyte, a process that is called white-to-brown fat switch (beige adipocyte), characterized by high expression of uncoupled protein 1 (UCP1). Beige adipocyte is responsible for energy expenditure and heat production, thereby is a potent way to resist obesity. We previously demonstrate that ablation of G protein-coupled receptor LGR4 promotes white-to-brown fat switch and significantly reduces body weight, based on which, we speculate that LGR4 ligand R-spondin1 may play the same role as LGR4 in beige adipocyte differentiation. We found that R-spondin1 treatment inhibited beige adipocyte differentiation from both mouse and human fat derived SVF. This effect was largely alleviated in the absence of LGR4, suggesting the effect of R-spondin1 in white-to-brown fat switch and energy metabolism may mediated by LGR4. We also established R-spondin1 knock out mouse and successfully obtained two mutant strains. In the present proposal, we aimed to comprehensively illustrate the effects of R-spondin1 on beige adipocyte differentiation and energy metabolism in vitro and in vitro by using models such as mouse and human adipose tissue derived SVF as well as R-spondin1 knock out mouse; to further study the molecular mechanism of R-spondin1’s effects on beige adipocyte and energy metabolism by LGR4 mutant mouse and its SVF. This study will provide scientific evidence for the role of R-spondin1 and its downstream signaling in energy metabolism, and its potential as new targets for anti-obesity therapy.

白色脂肪可转变为棕色脂肪即白色脂肪棕色化（米色脂肪），发挥产热耗能作用，是抵抗肥胖的重要途径。我们以往研究证实膜受体LGR4缺失促进白色脂肪棕色化、减轻体重，我们推测LGR4配体R-spondin1可能发挥类似作用，前期试验证明R-spondin1可抑制人和小鼠脂肪前体细胞SVF向米色脂肪分化，且该作用在LGR4缺失时大大削弱，提示R-spondin1可通过LGR4抑制白色脂肪棕色化，我们基于此建立了R-spondin1敲除小鼠。本项目将在此基础上利用小鼠和人脂肪原代SVF模型及Rspondin-1敲除小鼠从体外、体内水平证明Rspondin-1调节米色脂肪分化和能量代谢的作用；借助LGR4敲除小鼠及原代SVF从体内、体外水平阐明Rspondin-1发挥作用的分子机制，全面阐述Rspondin-1/LGR4信号通路在白色脂肪棕色化和能量平衡中的作用，为其作为肥胖干预靶点提供重要科学证据。

肥胖已成为蔓延全球的公共卫生问题，作为2型糖尿病、心血管疾病、癌症等慢性非传染性疾病（慢病）的重要危险因素，对肥胖的有效干预是控制慢病流行和爆发的重要环节。白色脂肪可转变为棕色脂肪即白色脂肪棕色化（米色脂肪），发挥产热耗能作用，是抵抗肥胖的重要途径。Rspondin1是经典Wnt信号通路调节分子，本项目建立R-spondin1基因敲除小鼠以及R-spondin1脂肪组织特异过表达小鼠，从体内水平证明Rspondin1抑制白色脂肪棕色化、抑制能量消耗、促进肥胖的重要作用，并且证明R-spondin1通过LGR4/beta-catenin信号通路调节白色脂肪棕色化机制，为肥胖干预提供新的靶点。未来开发针对R-spondin1及Wnt/β-catenin信号通路的抑制剂，有望在减肥药物开发中取得一定突破。