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 CTNNB1/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 serum amyloid A3 (Saa3), 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.

中文翻译：

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CTNNB1 /β-catenin功能异常通过调节成熟脂肪细胞和前脂肪细胞的串扰而促进肥胖。

营养过剩会导致肥胖和慢性炎症，并伴有白色脂肪组织（WAT）的膨胀。但是，控制脂肪量和肥胖的遗传因素仍未确定。我们在年轻的肥胖受试者中应用了全外显子测序，并发现了与肥胖风险增加相关的CTNNB1 /β-catenin罕见的功能获得性突变。β-catenin在成熟脂肪细胞中的特异性消融可减轻高脂饮食诱导的肥胖症，并减少sWAT的质量膨胀，同时减少Pdgfrα+前脂肪细胞的增殖和成熟脂肪细胞的数量。从机制上讲，β-连环蛋白通过成熟脂肪细胞中的β-连环素-TCF（T细胞特异性转录因子）复合物调节脂肪细胞来源的趋化因子血清淀粉样蛋白A3（Saa3）的转录，而Saa3活化的巨噬细胞可分泌多种因子，包括Pdgf-aa，这进一步促进了前脂肪细胞的增殖，表明β-catenin/ Saa3 /巨噬细胞可能介导sWAT中成熟的脂肪细胞-前脂肪细胞的串扰和脂肪膨胀。鉴定β-catenin作为脂肪增长和人类肥胖的关键调节剂，为开发靶向Wnt /β-catenin途径对抗肥胖的药物提供了基础。