Obesity has become epidemic worldwide, which triggers several obesity-associated complications. Obesity is characterized by excess fat storage mainly in the visceral white adipose tissue (vWAT), subcutaneous WAT (sWAT), and other tissues. Myriad studies have demonstrated the crucial role of canonical Wnt/β-catenin cascade in the development of organs and physiological homeostasis, whereas recent studies show that genetic variations/mutations in the Wnt/β-catenin pathway are associated with human metabolic diseases. In this review, we highlight the regulation of updated Wnt/β-catenin signaling in obesity, especially the distinctly depot-specific roles between subcutaneous and visceral adipose tissue under high-fed diet stimulation and WAT browning process.
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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