TLE3 is a dual-function transcriptional coregulator of adipogenesis

Cell Metab. 2011 Apr 6;13(4):413-427. doi: 10.1016/j.cmet.2011.02.014.

Abstract

PPARγ 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 PPARγ and Wnt pathways. TLE3 is a direct target of PPARγ that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPARγ activity and functions synergistically with PPARγ 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 β-catenin in preadipocytes, thereby inhibiting Wnt target gene expression and reversing β-catenin-dependent repression of adipocyte gene expression. Transgenic expression of TLE3 in adipose tissue in vivo mimics the effects of PPARγ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipogenesis / genetics*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cell Line
  • Co-Repressor Proteins
  • Dietary Fats / pharmacology
  • Gene Expression Regulation
  • Insulin Resistance
  • Mice
  • PPAR gamma / agonists
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Proteins / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Transcription Factor 4
  • Transcription, Genetic
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Co-Repressor Proteins
  • Dietary Fats
  • PPAR gamma
  • Proteins
  • RNA, Small Interfering
  • Tcf4 protein, mouse
  • Tle3 protein, mouse
  • Transcription Factor 4
  • Wnt Proteins
  • beta Catenin