SFRP5/β-Catenin信号通路在脂肪发育及体重调节中的作用

Canonical Wnt signaling pathway has been reported to be a negative regulator of adipogenesis in vitro, but the molecular mechanism and its in vivo involvement is not clear. Based on the previous study on Wnt signaling and energy metabolism in our center, we have established the adipose tissue specific β-Catenin knockout mouse model, which is now ready for use. By using this mouse model, in the present study, we will demonstrate the significant role and underlying mechanism of β-Catenin, the core member of Wnt signaling, in adipogenesis and body weight regulation in vivo. In addition, we have also found that the natural Wnt inhibitor SFRP5 was significantly higher expressed in the white adipose tissue of obese patients and mouse models than normal people and mice, respectively, while it showed reduced expression in lean mouse model. Besides, SFRP5 showed higher expression level in mature adipocytes than preadipocytes. Importantly, we have also found that SFRP5 overexpression increased the expression of canonical Wnt target genes. These results suggest that SFRP5 may promote adipogenesis and obesity by inhibiting canonical Wnt signaling. In this study, we will use β-Catenin knockout mouse model as well as primary cells and cell lines, and analyze the phenotypes of mice and cells after SFRP5 overexpression or knockdown, to demonstrate the important role of SFRP5 in fat development and body weight control. Lastly, we will compare the serum SFRP5 level between obese patients and normal individuals to establish SFRP5 to be a serum marker for obesity. Altogether, our study will provide a new candidate for the pathogenesis and therapy of obesity.

经典Wnt通路可抑制脂肪发育，但其整体水平作用机制尚不明确。本研究在以往Wnt通路和能量代谢研究基础上建立了脂肪组织特异性β-Catenin基因敲除小鼠模型，已进入大量繁殖阶段，并将在整体水平证明经典Wnt通路核心成员β-Catenin在脂肪发育和体重调节中的作用机制。我们前期研究发现Wnt通路天然抑制因子SFRP5在肥胖患者和小鼠脂肪组织表达显著增加，在偏瘦小鼠表达明显下降；成熟脂肪细胞表达显著高于前体细胞，且SFRP5可上调经典Wnt通路靶基因，表明其可能通过经典Wnt通路参与脂肪发育及肥胖发生。我们将借助脂肪特异性β-Catenin敲除小鼠和细胞模型，通过表型观察及SFRP5过表达或下调干预，从体内外水平阐明SFRP5通过抑制经典Wnt通路参与脂肪发育与体重调节；并检测肥胖和正常人群血清SFRP5水平，确立其为肥胖血清学预测指标。上述问题的阐明将为肥胖发生机制和干预研究提供重要靶点。

经典Wnt 通路可抑制脂肪发育，其天然抑制因子SFRP5在脂肪发育及肥胖发生中的作用尚存争议。本研究发现肥胖患者和小鼠脂肪组织中，SFRP5表达显著增加，并利用白色脂肪前体细胞（3T3-L1）和棕色脂肪原代细胞 (BAT SVF)两种模型阐明了SFRP5在成熟脂肪细胞中高表达，从而可用作新的成熟脂肪细胞标志基因。而利用过表达SFRP5的腺病毒感染3T3-L1细胞及BAT SVF，在体外水平发现过表达SFRP5对脂滴积聚、白色及棕色脂肪特异性标志基因表达无显著影响。这说明脂肪因子SFRP5在成熟脂肪细胞中的表达上调可能是脂肪分化所致的结果。我们证实在现有实验条件下，SFRP5的分泌方式主要是旁分泌而不是内分泌，SFRP5尚不能用作筛查人群肥胖症的血清学检测指标在分子水平。在体外水平，前体脂肪细胞中的SFRP5不通过经典Wnt/β-catenin信号通路发挥作用。在整体水平，本研究在以往Wnt 通路和能量代谢研究基础上成功建立了成熟脂肪组织特异性β-Catenin敲除小鼠（ABKO小鼠），并首次报道ABKO小鼠能抵抗高脂饮食诱导的肥胖发生和代谢恶化。以上结果为深化SFRP5及β-catenin在肥胖发生及脂肪发育中作用的认知提供了重要科学依据。