Transcriptional control of brown fat determination by PRDM16.
Brown fat cells are specialized to dissipate energy and can counteract obesity; however, the transcriptional basis of their determination is largely unknown. We show here that the zinc-finger protein PRDM16 is highly enriched in brown fat cells compared to white fat cells. When expressed in white fat cell progenitors, PRDM16 activates a robust brown fat phenotype including induction of PGC-1alpha, UCP1, and type 2 deiodinase (Dio2) expression and a remarkable increase in uncoupled respiration. Transgenic expression of PRDM16 at physiological levels in white fat depots stimulates the formation of brown fat cells. Depletion of PRDM16 through shRNA expression in brown fat cells causes a near total loss of the brown characteristics. PRDM16 activates brown fat cell identity at least in part by simultaneously activating PGC-1alpha and PGC-1beta through direct protein binding. These data indicate that PRDM16 can control the determination of brown fat fate.
Seale
Patrick
P
Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Kajimura
Shingo
S
Yang
Wenli
W
Chin
Sherry
S
Rohas
Lindsay M
LM
Uldry
Marc
M
Tavernier
Geneviève
G
Langin
Dominique
D
Spiegelman
Bruce M
BM
D041721:3T3-L1 Cells; D017667:Adipocytes; D052437:Adipocytes, Brown / Q000378:metabolism; D052438:Adipocytes, White / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002454:Cell Differentiation; D019069:Cell Respiration; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II
D004268:DNA-Binding Proteins; D007453:Iodide Peroxidase; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; C000604372:Ucp1 protein, mouse; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1