TRB3 suppresses adipocyte differentiation by negatively regulating PPARγ transcriptional activity

In the course of an effort to identify the regulators for peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent perilipin gene expression, we found that tribbles homolog 3 (TRB3), containing a single kinase domain without enzymatic activity, downregulates PPAR gamma transcriptional activities by protein-protein interaction. We examined the role that TRB3 plays in adipocyte differentiation in 3T3-LI cells. TRB3 gene and protein expression was increased during adipocyte differentiation concomitantly with an increase in the mRNA levels of CCAAT/enhancer binding protein homologous protein. The physical interaction between TRB3 and PPAR gamma was also verified in 3T3-LI adipocytes. Forced TRB3 expression in 3T3-LI cells decreased the mRNA levels of PPAR gamma-target genes and intracellular triglyceride levels, whereas knockdown of TRB3 expression by RNA interference increased them. TRB3 also inhibits PPAR gamma-dependent adipocyte differentiation in lentivirus-mediated PPAR gamma-expressing 3T3-LI cells. These results provide evidence that TRB3 acts as a potent negative regulator of PPAR gamma, a master regulator of adipocyte differentiation, and tightly controls adipogenesis.