title: Essential role for miR-196a in brown adipogenesis of white fat progenitor cells.
abstract: The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or β-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or β-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPβ, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPβ 3' regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPβ signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Gerardo
authors.initials: G
authors.lastname: Rodriguez-Araujo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nimura
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology*; D050156:Adipogenesis / Q000235:genetics*; D052436:Adipose Tissue, White / Q000166:cytology*; D050154:Adiposity / Q000235:genetics; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D000071256:Uncoupling Protein 1; D000099186:Histone Deacetylase 3
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D007473:Ion Channels; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D000071256:Uncoupling Protein 1; D000099186:Histone Deacetylase 3; C545012:CEBPB protein, human; C489815:HOXC8 protein, human; C542543:MIRN196 microRNA, human