title: MicroRNA 34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte fibroblast growth factor 21 signaling and SIRT1 function.
abstract: Brown fat generates heat through uncoupled respiration, protecting against hypothermia and obesity. Adult humans have brown fat, but the amounts and activities are substantially decreased in obesity, by unknown mechanisms. Here we show that elevated microRNA 34a (miR-34a) in obesity inhibits fat browning in part by suppressing the browning activators fibroblast growth factor 21 (FGF21) and SIRT1. Lentivirus-mediated downregulation of miR-34a in mice with diet-induced obesity reduced adiposity, improved serum profiles, increased the mitochondrial DNA copy number, and increased oxidative function in adipose tissue in both BALB/c and C57BL/6 mice. Remarkably, downregulation of miR-34a increased coexpression of the beige fat-specific marker CD137 and the browning marker UCP1 in all types of white fat, including visceral fat, and promoted additional browning in brown fat. Mechanistically, downregulation of miR-34a increased expression of the FGF21 receptor components, FGFR1 and βKL, and also that of SIRT1, resulting in FGF21/SIRT1-dependent deacetylation of PGC-1α and induction of the browning genes Ucp1, Pgc-1α, and Prdm16. Importantly, anti-miR-34a-mediated beneficial effects, including decreased adiposity, are likely from multiple tissues, since downregulation of miR-34a also improves hepatic FGF21 signaling and lipid oxidation. This study identifies miR-34a as an inhibitor of beige and brown fat formation, providing a potential target for treating obesity-related diseases.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Fu
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Seok
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Sunge
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Suino-Powell
authors.affiliation: Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA jongsook@illinois.edu.
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology*; D050154:Adiposity; D000818:Animals; D015536:Down-Regulation; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1