TLE3 is a dual-function transcriptional coregulator of adipogenesis.

ABSTRACT: PPAR? and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identify the groucho family member TLE3 as a transcriptional integrator of the PPAR? and Wnt pathways. TLE3 is a direct target of PPAR? that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPAR? activity and functions synergistically with PPAR? on its target promoters to stimulate adipogenesis. At the same time, induction of TLE3 during differentiation provides a mechanism for termination of Wnt signaling. TLE3 antagonizes TCF4 activation by ?-catenin in preadipocytes, thereby inhibiting Wnt target gene expression and reversing ?-catenin-dependent repression of adipocyte gene expression. Transgenic expression of TLE3 in adipose tissue in vivo mimics the effects of PPAR? agonist and ameliorates high-fat-diet-induced insulin resistance. Our data suggest that TLE3 acts as a dual-function switch, driving the formation of both active and repressive transcriptional complexes that facilitate the adipogenic program.

SUBMITTER: Villanueva CJ 

PROVIDER: S-EPMC3089971 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature