title: TLE3 is a dual-function transcriptional coregulator of adipogenesis.
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.
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Claudio J
authors: CJ
authors: Villanueva
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Hironori
authors: H
authors: Waki
authors: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Cristina
authors: C
authors: Godio
authors: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors: Ronni
authors: R
authors: Nielsen
authors: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Wen-Ling
authors: WL
authors: Chou
authors: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors: Leo
authors: L
authors: Vargas
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Kevin
authors: K
authors: Wroblewski
authors: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors: Christian
authors: C
authors: Schmedt
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Lily C
authors: LC
authors: Chao
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Rima
authors: R
authors: Boyadjian
authors: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors: Susanne
authors: S
authors: Mandrup
authors: Department of Medicine, Division of Endocrinology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Andrea
authors: A
authors: Hevener
authors: Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: esaez@scripps.edu.
authors: Enrique
authors: E
authors: Saez
authors: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ptontonoz@mednet.ucla.edu.
authors: Peter
authors: P
authors: Tontonoz
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D056970:Co-Repressor Proteins; D004041:Dietary Fats / Q000494:pharmacology; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D056970:Co-Repressor Proteins; D004041:Dietary Fats; D047495:PPAR gamma; D011506:Proteins; D034741:RNA, Small Interfering; C090743:Tcf4 protein, mouse; C104849:Tle3 protein, mouse; D000073940:Transcription Factor 4; D051153:Wnt Proteins; D051176:beta Catenin