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

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/?-catenin associated with increased obesity risk. Specific ablation of ?-catenin in mature adipocytes attenuated high-fat diet-induced obesity and reduced sWAT mass expansion with less proliferated Pdgfr?+ preadipocytes and less mature adipocytes. Mechanistically, ?-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ?-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 ?-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ?-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/?-catenin pathway to combat obesity.

SUBMITTER: Chen M 

PROVIDER: S-EPMC6949042 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature