title: Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity.
abstract: Uncoupling protein 1 (Ucp1) contributes to thermogenesis, and its expression is regulated at the transcriptional level. Here, we show that Ucp1 expression is also regulated post-transcriptionally. In inguinal white adipose tissue (iWAT) of mice fed a high-fat diet (HFD), Ucp1 level decreases concomitantly with increases in Cnot7 and its interacting partner Tob. HFD-fed mice lacking Cnot7 and Tob express elevated levels of Ucp1 mRNA in iWAT and are resistant to diet-induced obesity. Ucp1 mRNA has an elongated poly(A) tail and persists in iWAT of Cnot7(-/-) and/or Tob(-/-) mice on a HFD. Ucp1 3'-UTR-containing mRNA is more stable in cells expressing mutant Tob that is unable to bind Cnot7 than in WT Tob-expressing cells. Tob interacts with BRF1, which binds to an AU-rich element in the Ucp1 3'-UTR. BRF1 knockdown partially restores the stability of Ucp1 3'-UTR-containing mRNA. Thus, the Cnot7-Tob-BRF1 axis inhibits Ucp1 expression and contributes to obesity.
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Shungo
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Tokumasu
authors.affiliation: Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412, Japan. Electronic address: tadashi.yamamoto@oist.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D051817:Butyrate Response Factor 1; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005095:Exoribonucleases; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D055550:Protein Stability; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012260:Ribonucleases; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: C441028:BRF1 protein, human; D051817:Butyrate Response Factor 1; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D035381:TATA-Binding Protein Associated Factors; C098669:TOB1 protein, human; C490903:Tob1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000071256:Uncoupling Protein 1; C488431:Zfp36l1 protein, mouse; C545829:CNOT7 protein, human; C489778:Cnot7 protein, mouse; D005095:Exoribonucleases; D012260:Ribonucleases
keywords: Cnot7; Tob; Ucp1; deadenylation; obesity