title: The transcriptional modulator Ifrd1 controls PGC-1α expression under short-term adrenergic stimulation in brown adipocytes.
abstract: Sympathetic tone activates the function of classical brown adipocytes, which constitutively exist in the brown adipose tissue (BAT), and inducible brown adipocytes (so-called beige adipocytes), which sporadically reside within the white adipose tissue (WAT). Here we identified the transcriptional modulator interferon-related developmental regulator 1 (Ifrd1) as a negative regulator of thermogenic and mitochondrial gene expression in brown adipocytes. Ifrd1 expression was markedly induced by cold exposure and administration of CL-316243 (a β3 adrenergic agonist) in interscapular brown adipose and inguinal subcutaneous WATs, but not in epididymal visceral WAT, in vivo. Adrenergic stimulation also induced Ifrd1 expression in brown adipocytes in a cAMP responsive element binding protein-dependent manner in vitro. CL-316243 injection markedly elevated thermogenic and mitochondrial gene expression, including peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1a) in the subcutaneous WAT of Ifrd1 knockout mice compared with gene expression in wild-type mice. Pgc1a promoter activity enhanced by the transcription factor specificity protein 1 (Sp1) was markedly repressed by co-introduction of Ifrd1 in brown adipocytes, whereas the repression was markedly prevented by the addition of trichostatin A, a histone deacetylase inhibitor. Moreover, adrenergic stimulation induced complex formation between Ifrd1, Sp1 and mSIN3B, which is a component of the SIN complex containing histone deacetylase, in brown adipocytes. These findings, therefore, suggest that Ifrd1 could be a pivotal negative regulator of sympathetic regulation of thermogenic and mitochondrial gene expression in brown adipocytes by interacting with Sp1 and the mSIN3 complex.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Gyujin
authors.initials: G
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Horie
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanayama
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukasawa
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iezaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Onishi
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Kakeru
authors.initials: K
authors.lastname: Ozaki
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takarada
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000322:Adrenergic Agonists / Q000008:administration & dosage; D000818:Animals; D003080:Cold Temperature; D004149:Dioxoles / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis / Q000235:genetics*
chemical_list: D000322:Adrenergic Agonists; D004149:Dioxoles; C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012097:Repressor Proteins; C115812:Sin3b protein, mouse; D016329:Sp1 Transcription Factor; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate
keywords: Ifrd1; PGC-1α; Sp1; brown adipocyte; sympathetic tone