Modulation of adipogenesis using citric acids cycle metabolites and vitamin C via controlling TET protein activity

Abstract

Adipogenesis refers to the cellular differentiation of preadipocyte into adipocyte in the presence of adipogenic stimuli. In this study, we showed the roles of vitamin C and two citric acids cycle (CAC) metabolites, succinate and fumarate, during 3T3‐L1 adipocyte differentiation. TET proteins are Fe(II) and α‐ketoglutarate (α‐KG) dependent dioxygenases, which can convert 5‐methylcytosine (5‐mC) to 5‐hydroxymethylcytosine (5‐hmC) in DNA. They have been described as key epigenetic modulators for cellular development by removing DNA methylation in locus specific and genome‐wide levels and generating 5‐hmC, an intermediate for oxidative demethylation. Vitamin C enhances TET protein activity presumably by maintaining the ferrous state of iron while succinate and fumarate inhibit its activity by competiting with α‐KG. We found that treatment of vitamin C in 3T3‐L1 cells enhanced TET protein activity while succinate and fumarate repressed it showing increased and reduced level of global 5‐hmC, respectively. Furthermore, we found that treatment of vitamin C directly promoted the adipogenesis by upregulating the Pparγ expression, a master regulator for adipogenesis via enhanced demethylation of Pparγ region. On the other hands, treatment of fumarate directly repressed the accumulation of lipid droplets by preserving the methylated status at the Pparγ region. Together, the results demonstrated that development of adipocyte may be epigenetically modulated by CAC metabolites and vitamin C via controlling the TET protein activity.