Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARgamma and hypoxia

摘要

Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo(Fra-2~(DELTAadip) mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2~(DELTAadip) mice. At the molecular level, Fra-2 directly binds to the PPARgamma2 promoter and represses PPARgamma2 expression. Deletion of Fra-2 leads to increased PPARgamma2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.