MiR-27 orchestrates the transcriptional regulation of brown adipogenesis.
OBJECTIVE
Brown adipose tissue (BAT) produces heat using chemical energy of lipids and glucose, a function induced by cold exposure or diet. The brown adipogenesis is tightly controlled in a coordinated interplay between several transcriptional factors. It is not known what enables and coordinates this robust program of concerted cooperation between the transcriptional factors and co-regulators necessary for the brown adipogenesis.


METHODS
A. In vivo studies--we investigated the expression levels of miR-27a and b in mice after cold exposure. B. Using gene expression and functional studies together with high throughput imaging in primary preadipocytes, and cell culture models, we investigated the role of miR-27 in beige and brown adipogenesis. C. Using gene silencing and rescue experiments we dissected the molecular mechanisms of the miR-27 action.


RESULTS
After cold exposure, miR-27 is downregulated in BAT and subcutaneous white adipose tissue (SAT). MiR-27 is also downregulated during brown adipogenesis of primary preadipocytes in vitro, and it directly targets and negatively regulates the essential components of the brown transcriptional network: Prdm16, Pparα, Creb, and in part Pgc1β. Together with its direct effect on Pparγ, and indirect on Pgc1α, mir-27 decreases brown differentiation of cultured cells and of primary SAT preadipocytes.


CONCLUSIONS
Our results point to miR-27 as a central upstream regulator of the transcriptional network involved in beige and brown adipogenesis after cold exposure, and suggest miR-27 inhibition as a novel therapeutic approach for metabolic diseases aiming at increasing the beige/brown fat mass.
Duke-NUS Medical School Singapore, 8 College Rd, 169857, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science,Technology and Research, 61 Biopolis Drive, 138673, Singapore.
Lei
L
Sun
University of Geneva, Medical Faculty, Department of Cell Physiology and Metabolism, Centre Médical Universitaire (CMU), 1211 Geneva 4, Switzerland; University College London (UCL), Division of Biosciences, School of Life and Medical Sciences, Institute of Structural and Molecular Biology, Darwin Building, Gower Street, WC1E 6BT, London, UK. Electronic address: Mirko.Trajkovski@unige.ch.
Mirko
M
Trajkovski
D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003080:Cold Temperature; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015347:RNA Probes; D060888:Real-Time Polymerase Chain Reaction; D050151:Subcutaneous Fat / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D015347:RNA Probes; D014157:Transcription Factors
3′ untranslated region; 3′UTR; Adipocyte protein 2 (Fabp4, Fatty acid binding protein 4); Adipogenesis; Adrb3; BAT; Beige; Brown; Brown adipose tissue; C/EBPs; CCAAT/enhancer-binding proteins; Creb; Cyclic adenosine monophosphate; Fat; IBMX; Mouse Primary Immortalized Brown Adipocytes; Myf5; Myogenic factor 5; OCR; PIBA; PPARγ-coactivators-1; PRDI-BF1-RIZ1 (PR) domain containing 16; Peroxisome proliferator-activated receptor-a and γ; Pgc1; Pparα and γ; Prdm16; SAT; SVF; Subcutaneous adipose tissue; Ucp1; Uncoupling protein 1; VAT; Visceral adipose tissue; WAT; White adipose tissue; aP2; beta-3 adrenergic receptor; cAMP; cAMP responsive element binding protein; isobutylmethylxanthine; miRNAs; microRNAs; oxygen consumption rates; primary stromal–vascular fraction