title: Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid storage versus thermogenic gene programs.
abstract: Transcriptional effectors of white adipocyte-selective gene expression have not been described. Here we show that TLE3 is a white-selective cofactor that acts reciprocally with the brown-selective cofactor Prdm16 to specify lipid storage and thermogenic gene programs. Occupancy of TLE3 and Prdm16 on certain promoters is mutually exclusive, due to the ability of TLE3 to disrupt the physical interaction between Prdm16 and PPARγ. When expressed at elevated levels in brown fat, TLE3 counters Prdm16, suppressing brown-selective genes and inducing white-selective genes, resulting in impaired fatty acid oxidation and thermogenesis. Conversely, mice lacking TLE3 in adipose tissue show enhanced thermogenesis in inguinal white adipose depots and are protected from age-dependent deterioration of brown adipose tissue function. Our results suggest that the establishment of distinct adipocyte phenotypes with different capacities for thermogenesis and lipid storage is accomplished in part through the cell-type-selective recruitment of TLE3 or Prdm16 to key adipocyte target genes.
authors.affiliation: Howard Hughes Medical Institute, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Villanueva
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Jiexin
authors.initials: J
authors.lastname: Wang
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Yiping
authors.initials: Y
authors.lastname: Tu
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.forename: Xu
authors.initials: X
authors.lastname: Peng
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Kevin
authors.initials: K
authors.lastname: Wroblewski
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010084:Oxidation-Reduction; D047495:PPAR gamma / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D047495:PPAR gamma; C521133:Prdm16 protein, mouse; D011506:Proteins; C104849:Tle3 protein, mouse; D014157:Transcription Factors