Research ArticleCELL BIOLOGY

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

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Science Advances  08 Jan 2020:
Vol. 6, no. 2, eaax9605
DOI: 10.1126/sciadv.aax9605

Abstract

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.

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