CTNNB1/ β -catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes

• Published in: Science advances 2020-01, Vol.6 (2), p.eaax9605-eaax9605
• Main Authors: Chen, Maopei, Lu, Peng, Ma, Qinyun, Cao, Yanan, Chen, Na, Li, Wen, Zhao, Shaoqian, Chen, Banru, Shi, Juan, Sun, Yingkai, Shen, Hongbin, Sun, Liangdan, Shen, Juan, Liao, Qijun, Zhang, Yifei, Hong, Jie, Gu, Weiqiong, Liu, Ruixin, Ning, Guang, Wang, Weiqing, Wang, Jiqiu
• Format: Article
• Language: English
• Subjects: Cell Biology; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aax9605

Overnutrition results in adiposity and chronic inflammation with expansion of white adipose tissue (WAT). However, genetic factors controlling fat mass and adiposity remain largely undetermined. We applied whole-exome sequencing in young obese subjects and identified rare gain-of-function mutations in β-catenin associated with increased obesity risk. Specific ablation of β-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfrα preadipocytes and less mature adipocytes. Mechanistically, β-catenin regulated the transcription of ( ), an adipocyte-derived chemokine, through β-catenin-TCF (T-Cell-Specific Transcription Factor) complex in mature adipocytes, and Saa3 activated macrophages to secrete several factors, including Pdgf-aa, which further promoted the proliferation of preadipocytes, suggesting that β-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of β-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/β-catenin pathway to combat obesity.