CTNNB1/ß-catenin dysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes.
Sci Adv
; 6(2): eaax9605, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31934629
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/ß-catenin associated with increased obesity risk. Specific ablation of ß-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, ß-catenin regulated the transcription of serum amyloid A3 (Saa3), an adipocyte-derived chemokine, through ß-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 ß-catenin/Saa3/macrophages may mediate mature adipocyte-preadipocyte cross-talk and fat expansion in sWAT. The identification of ß-catenin as a key regulator in fat expansion and human adiposity provides the basis for developing drugs targeting Wnt/ß-catenin pathway to combat obesity.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diferenciación Celular
/
Adipocitos
/
Beta Catenina
/
Adiposidad
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Adv
Año:
2020
Tipo del documento:
Article