Abstract
Adipocytes differentiate from mesenchymal stem cells (MSCs) in a process known as adipogenesis. The programme of adipogenesis is regulated by the sequential activation of transcription factors and several signaling pathways. There is growing evidence indicating that a class of small non-coding single-stranded RNAs known as “microRNAs (miRNAs)” also are involved in this process. In this review, we summarize the biology and functional mechanisms of miRNAs in adipocyte differentiation. In addition, we further discuss the miRNAs profiling, the miRNAs function and miRNAs target prediction in the adipogenesis.
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Gesta S, Tseng YH, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 2007; 131(2): 242–256
Otto TC, Lane MD. Adipose development: from stem cell to adipocyte. Crit Rev Biochem Mol Biol 2005; 40(4): 229–242
Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev 1998; 78(3): 783–809
Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev 2000; 14(11): 1293–1307
MacDougald OA, Mandrup S. Adipogenesis: forces that tip the scales. Trends Endocrinol Metab 2002; 13(1): 5–11
Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 2002; 3(1): 25–38
Smith PJ, Wise LS, Berkowitz R, Wan C, Rubin CS. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. J Biol Chem 1988; 263(19): 9402–9408
Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005; 6(5): 376–385
[No authors listed]. Obesity: preventing and managing the global epidemic. Report of a WHO consultation.World Health Organ Tech Rep Ser 2000; 894: i–xii, 1–253
Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP, Luo XH. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 2009; 119(12): 3666–3677
He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5(7): 522–531
Yang L, Cheng P, Chen C, He HB, Xie GQ, Zhou HD, Xie H, Wu XP, Luo XH. miR-93/Sp7 function loop mediates osteoblast mineralization. J Bone Miner Res 2012; 27(7): 1598–1606
Hu R, Liu W, Li H, Yang L, Chen C, Xia ZY, Guo LJ, Xie H, Zhou HD, Wu XP, Luo XH. A Runx2/miR-3960/miR-2861 regulatory feedback loop during mouse osteoblast differentiation. J Biol Chem 2011; 286(14): 12328–12339
Li H, Li WX, Ding SW. Induction and suppression of RNA silencing by an animal virus. Science 2002; 296(5571): 1319–1321
Zeng Y, Yi R, Cullen BR. MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA 2003; 100(17): 9779–9784
Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature 2003; 425(6956): 415–419
Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003; 17(24): 3011–3016
Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science 2004; 303(5654): 95–98
Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R. The Microprocessor complex mediates the genesis of microRNAs. Nature 2004; 432(7014): 235–240
Tan GS, Garchow BG, Liu X, Yeung J, Morris JP 4th, Cuellar TL, McManus MT, Kiriakidou M. Expanded RNA-binding activities of mammalian Argonaute 2. Nucleic Acids Res 2009; 37(22): 7533–7545
Hutvágner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science 2002; 297(5589): 2056–2060
Pillai RS, Bhattacharyya SN, Filipowicz W. Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 2007; 17(3): 118–126
Shingara J, Keiger K, Shelton J, Laosinchai-Wolf W, Powers P, Conrad R, Brown D, Labourier E. An optimized isolation and labeling platform for accurate microRNA expression profiling. RNA 2005; 11(9): 1461–1470
Hilton C, Neville MJ. Karpe F. MicroRNAs in adipose tissue: their role in adipogenesis and obesity. Int J Obes (Lond) 2013; 37: 325–332
Castoldi M, Schmidt S, Benes V, Noerholm M, Kulozik AE, Hentze MW, Muckenthaler MU. A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA). RNA 2006; 12(5): 913–920
Válóczi A, Hornyik C, Varga N, Burgyán J, Kauppinen S, Havelda Z. Sensitive and specific detection of microRNAs by northern blot analysis using LNA-modified oligonucleotide probes. Nucleic Acids Res 2004; 32(22): e175
Neville MJ, Collins JM, Gloyn AL, McCarthy MI, Karpe F. Comprehensive human adipose tissue mRNA and microRNA endogenous control selection for quantitative real-time-PCR normalization. Obesity (Silver Spring) 2011; 19(4): 888–892
Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 2009; 10(1): 57–63
Lee EJ, Baek M, Gusev Y, Brackett DJ, Nuovo GJ, Schmittgen TD. Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors. RNA 2008; 14(1): 35–42
Kajimoto K, Naraba H, Iwai N. MicroRNA and 3T3-L1 pre-adipocyte differentiation. RNA 2006; 12(9): 1626–1632
Xie H, Lim B, Lodish HF. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 2009; 58(5): 1050–1057
Ailhaud G, Grimaldi P, Négrel R. Cellular and molecular aspects of adipose tissue development. Annu Rev Nutr 1992; 12(1): 207–233
Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 2000; 16(1): 145–171
Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7(12): 885–896
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79(7): 1147–1156
Tamori Y, Masugi J, Nishino N, Kasuga M. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes 2002; 51(7): 2045–2055
Hamm JK, Park BH, Farmer SR. A role for C/EBPbeta in regulating peroxisome proliferator-activated receptor gamma activity during adipogenesis in 3T3-L1 preadipocytes. J Biol Chem 2001; 276(21): 18464–18471
Shao D, Lazar MA. Peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein alpha, and cell cycle status regulate the commitment to adipocyte differentiation. J Biol Chem 1997; 272(34): 21473–21478
Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD, MacDougald OA. Regulation of Wnt signaling during adipogenesis. J Biol Chem 2002; 277(34): 30998–31004
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289(5481): 950–953
Arango NA, Szotek PP, Manganaro TF, Oliva E, Donahoe PK, Teixeira J. Conditional deletion of beta-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium. Dev Biol 2005; 288(1): 276–283
Choy L, Skillington J, Derynck R. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation. J Cell Biol 2000; 149(3): 667–682
Spiegelman BM, Ginty CA. Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 1983; 35(3 Pt 2): 657–666
Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126(4): 677–689
Xu P, Vernooy SY, Guo M, Hay BA. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol 2003; 13(9): 790–795
Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, Sun Y, Koo S, Perera RJ, Jain R, Dean NM, Freier SM, Bennett CF, Lollo B, Griffey R. MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 2004; 279(50): 52361–52365
Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell 2008; 133(2): 217–222
Wang Q, Li YC, Wang J, Kong J, Qi Y, Quigg RJ, Li X. miR-17-92 cluster accelerates adipocyte differentiation by negatively regulating tumor-suppressor Rb2/p130. Proc Natl Acad Sci USA 2008; 105(8): 2889–2894
Richon VM, Lyle RE, McGehee RE Jr. Regulation and expression of retinoblastoma proteins p107 and p130 during 3T3-L1 adipocyte differentiation. J Biol Chem 1997; 272(15): 10117–10124
Prince AM, May JS, Burton GR, Lyle RE, McGehee RE Jr. Proteasomal degradation of retinoblastoma-related p130 during adipocyte differentiation. Biochem Biophys Res Commun 2002; 290(3): 1066–1071
Kim YJ, Hwang SJ, Bae YC, Jung JS. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue. Stem Cells 2009; 27(12): 3093–3102
Kim YJ, Hwang SH, Cho HH, Shin KK, Bae YC, Jung JS. MicroRNA 21 regulates the proliferation of human adipose tissuederived mesenchymal stem cells and high-fat diet-induced obesity alters microRNA 21 expression in white adipose tissues. J Cell Physiol 2012; 227(1): 183–193
Martinelli R, Nardelli C, Pilone V, Buonomo T, Liguori R, Castanò I, Buono P, Masone S, Persico G, Forestieri P, Pastore L, Sacchetti L. miR-519d overexpression is associated with human obesity. Obesity (Silver Spring) 2010; 18(11): 2170–2176
Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289(5481): 950–953
Kennell JA, Gerin I, MacDougald OA, Cadigan KM. The microRNA miR-8 is a conserved negative regulator of Wnt signaling. Proc Natl Acad Sci USA 2008; 105(40): 15417–15422
Qin L, Chen Y, Niu Y, Chen W, Wang Q, Xiao S, Li A, Xie Y, Li J, Zhao X, He Z, Mo D. A deep investigation into the adipogenesis mechanism: profile of microRNAs regulating adipogenesis by modulating the canonical Wnt/beta-catenin signaling pathway. BMC Genomics 2010; 11(1): 320
Zaragosi LE, Wdziekonski B, Brigand KL, Villageois P, Mari B, Waldmann R, Dani C, Barbry P. Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis. Genome Biol 2011; 12(7): R64
Huang J, Zhao L, Xing L, Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells 2010; 28(2): 357–364
Ling HY, Wen GB, Feng SD, Tuo QH, Ou HS, Yao CH, Zhu BY, Gao ZP, Zhang L, Liao DF. MicroRNA-375 promotes 3T3-L1 adipocyte differentiation through modulation of extracellular signal-regulated kinase signalling. Clin Exp Pharmacol Physiol 2011; 38(4): 239–246
Lin Q, Gao Z, Alarcon RM, Ye J, Yun Z. A role of miR-27 in the regulation of adipogenesis. FEBS J 2009; 276(8): 2348–2358
Kim SY, Kim AY, Lee HW, Son YH, Lee GY, Lee JW, Lee YS, Kim JB. miR-27a is a negative regulator of adipocyte differentiation via suppressing PPARgamma expression. Biochem Biophys Res Commun 2010; 392(3): 323–328
Karbiener M, Fischer C, Nowitsch S, Opriessnig P, Papak C, Ailhaud G, Dani C, Amri EZ, Scheideler M. microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma. Biochem Biophys Res Commun 2009; 390(2): 247–251
Lee EK, Lee MJ, Abdelmohsen K, Kim W, Kim MM, Srikantan S, Martindale JL, Hutchison ER, Kim HH, Marasa BS, Selimyan R, Egan JM, Smith SR, Fried SK, Gorospe M. miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression. Mol Cell Biol 2011; 31(4): 626–638
Sun T, Fu M, Bookout AL, Kliewer SA, Mangelsdorf DJ. MicroRNA let-7 regulates 3T3-L1 adipogenesis. Mol Endocrinol 2009; 23(6): 925–931
Anand A, Chada K. In vivo modulation of Hmgic reduces obesity. Nat Genet 2000; 24(4): 377–380
Kinoshita M, Ono K, Horie T, Nagao K, Nishi H, Kuwabara Y, Takanabe-Mori R, Hasegawa K, Kita T, Kimura T. Regulation of adipocyte differentiation by activation of serotonin (5-HT) receptors 5-HT2AR and 5-HT2CR and involvement of microRNA-448-mediated repression of KLF5. Mol Endocrinol 2010; 24(10): 1978–1987
Rajewsky N. microRNA target predictions in animals. Nat Genet 2006; 38( Suppl): S8–S13
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. Human MicroRNA targets. PLoS Biol 2004; 2(11): e363
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell 2003; 115(7): 787–798
Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N. Combinatorial microRNA target predictions. Nat Genet 2005; 37(5): 495–500
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120(1): 15–20
Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell 2006; 126(6): 1203–1217
Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433(7027): 769–773
Wang X, Wang X. Systematic identification of microRNA functions by combining target prediction and expression profiling. Nucleic Acids Res 2006; 34(5): 1646–1652
Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455(7209): 64–71
Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C, Mourelatos Z, Hatzigeorgiou A. A combined computational-experimental approach predicts human microRNA targets. Genes Dev 2004; 18(10): 1165–1178
Chi SW, Zang JB, Mele A, Darnell RB. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 2009; 460(7254): 479–486
Stenvang J, Kauppinen S. MicroRNAs as targets for antisense-based therapeutics. Expert Opin Biol Ther 2008; 8(1): 59–81
Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007; 4(9): 721–726
Liu Z, Sall A, Yang D. MicroRNA: An emerging therapeutic target and intervention tool. Int J Mol Sci 2008; 9(6): 978–999
Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005; 438(7068): 685–689
Elmén J, Lindow M, Schütz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjärn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S. LNA-mediated microRNA silencing in non-human primates. Nature 2008; 452(7189): 896–899
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Zhang, R., Wang, D., Xia, Z. et al. The role of microRNAs in adipocyte differentiation. Front. Med. 7, 223–230 (2013). https://doi.org/10.1007/s11684-013-0252-8
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DOI: https://doi.org/10.1007/s11684-013-0252-8