MicroRNA regulatory networks in human adipose tissue and obesity (original) (raw)

• Haslam, D. W. & James, W. P. Obesity. Lancet 366, 1197–1209 (2005).
  Article PubMed Google Scholar
• Chen, L., Magliano, D. J. & Zimmet, P. Z. The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat. Rev. Endocrinol. 8, 228–236 (2012).
  Article CAS Google Scholar
• Prentice, A. M. The emerging epidemic of obesity in developing countries. Int. J. Epidemiol. 35, 93–99 (2006).
  Article PubMed Google Scholar
• Bray, G. A. & Tartaglia, L. A. Medicinal strategies in the treatment of obesity. Nature 404, 672–677 (2000).
  Article CAS PubMed Google Scholar
• Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896 (2006).
  Article CAS PubMed Google Scholar
• Arner, E. & Arner, P. Health and obesity: not just skin deep. Science 342, 558–559 (2013).
  Article CAS PubMed Google Scholar
• Arner, P. Not all fat is alike. Lancet 351, 1301–1302 (1998).
  Article CAS PubMed Google Scholar
• Arner, P. & Langin, D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol. Metab. 25, 255–262 (2014).
  Article CAS PubMed Google Scholar
• Johnson, A. M. & Olefsky, J. M. The origins and drivers of insulin resistance. Cell 152, 673–684 (2013).
  Article CAS PubMed Google Scholar
• Turer, A. T. & Scherer, P. E. Adiponectin: mechanistic insights and clinical implications. Diabetologia 55, 2319–2326 (2012).
  Article CAS PubMed Google Scholar
• Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
  CAS PubMed Google Scholar
• Rosen, E. D. & Spiegelman, B. M. Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16, 145–171 (2000).
  Article CAS PubMed Google Scholar
• Arner, P. et al. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 478, 110–113 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Ryden, M., Andersson, D. P., Bernard, S., Spalding, K. & Arner, P. Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects. J. Lipid Res. 54, 2909–2913 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
  Article CAS PubMed Google Scholar
• Nuutila, P. Brown adipose tissue thermogenesis in humans. Diabetologia 56, 2110–2112 (2013).
  Article CAS PubMed Google Scholar
• Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).
  Article CAS PubMed Google Scholar
• Mukherji, S. et al. MicroRNAs can generate thresholds in target gene expression. Nat. Genet. 43, 854–859 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Lu, J. & Clark, A. G. Impact of microRNA regulation on variation in human gene expression. Genome Res. 22, 1243–1254 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152–D157 (2011).
  Article CAS PubMed Google Scholar
• Huang, J. C. et al. Using expression profiling data to identify human microRNA targets. Nat. Methods 4, 1045–1049 (2007).
  Article CAS PubMed Google Scholar
• Ulitsky, I., Laurent, L. C. & Shamir, R. Towards computational prediction of microRNA function and activity. Nucleic Acids Res. 38, e160 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Gennarino, V. A. et al. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res. 22, 1163–1172 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Huang, G. T., Athanassiou, C. & Benos, P. V. mirConnX: condition-specific mRNA–microRNA network integrator. Nucleic Acids Res. 39, W416–W423 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Jayaswal, V., Lutherborrow, M., Ma, D. D. & Yang, Y. H. Identification of microRNA–mRNA modules using microarray data. BMC Genomics 12, 138 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Le Bechec, A. et al. MIR@NT@N: a framework integrating transcription factors, microRNAs and their targets to identify sub-network motifs in a meta-regulation network model. BMC Bioinformatics 12, 67 (2011).
  Article PubMed PubMed Central Google Scholar
• Xu, J. et al. MiRNA–miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features. Nucleic Acids Res. 39, 825–836 (2011).
  Article CAS PubMed Google Scholar
• Kuhn, D. E. et al. Experimental validation of miRNA targets. Methods 44, 47–54 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Xie, H., Lim, B. & Lodish, H. F. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 58, 1050–1057 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Arner, E. et al. Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes 61, 1986–1993 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Heneghan, H. M., Miller, N., McAnena, O. J., O'Brien, T. & Kerin, M. J. Differential miRNA expression in omental adipose tissue and in the circulation of obese patients identifies novel metabolic biomarkers. J. Clin. Endocrinol. Metab. 96, E846–E850 (2011).
  Article CAS PubMed Google Scholar
• Keller, P. et al. Gene-chip studies of adipogenesis-regulated microRNAs in mouse primary adipocytes and human obesity. BMC Endocr. Disord. 11, 7 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Martinelli, R. et al. miR-519d overexpression is associated with human obesity. Obesity (Silver Spring) 18, 2170–2176 (2010).
  Article CAS Google Scholar
• Meerson, A. et al. Human adipose microRNA-221 is upregulated in obesity and affects fat metabolism downstream of leptin and TNFα. Diabetologia 56, 1971–1979 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Ortega, F. J. et al. MiRNA expression profile of human subcutaneous adipose and during adipocyte differentiation. PLoS ONE 5, e9022 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Capobianco, V. et al. miRNA and protein expression profiles of visceral adipose tissue reveal miR-141/YWHAG and miR-520e/RAB11A as two potential miRNA/protein target pairs associated with severe obesity. J. Proteome Res. 11, 3358–3369 (2012).
  Article CAS PubMed Google Scholar
• Chen, L. et al. MiR-146b is a regulator of human visceral preadipocyte proliferation and differentiation and its expression is altered in human obesity. Mol. Cell. Endocrinol. 393, 65–74 (2014).
  Article CAS PubMed Google Scholar
• Chou, W. W. et al. Decreased microRNA-221 is associated with high levels of TNFα in human adipose tissue-derived mesenchymal stem cells from obese woman. Cell Physiol. Biochem. 32, 127–137 (2013).
  Article CAS PubMed Google Scholar
• Diawara, M. R. et al. Adaptive expression of microRNA-125a in adipose tissue in response to obesity in mice and men. PLoS ONE 9, e91375 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Oger, F. et al. Cell-specific dysregulation of microRNA expression in obese white adipose tissue. J. Clin. Endocrinol. Metab. 99, 2821–2833 (2014).
  Article CAS PubMed Google Scholar
• Dahlman, I. et al. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor α. Diabetes 55, 1792–1799 (2006).
  Article CAS PubMed Google Scholar
• Klimcakova, E. et al. Worsening of obesity and metabolic status yields similar molecular adaptations in human subcutaneous and visceral adipose tissue: decreased metabolism and increased immune response. J. Clin. Endocrinol. Metab. 96, E73–E82 (2011).
  Article CAS PubMed Google Scholar
• Hilton, C., Neville, M. J. & Karpe, F. MicroRNAs in adipose tissue: their role in adipogenesis and obesity. Int. J. Obesity 37, 325–332 (2013).
  Article CAS Google Scholar
• Neville, M. J., Collins, J. M., Gloyn, A. L., McCarthy, M. I. & Karpe, F. Comprehensive human adipose tissue mRNA and microRNA endogenous control selection for quantitative real-time-PCR normalization. Obesity (Silver Spring) 19, 888–892 (2011).
  Article CAS Google Scholar
• Civelek, M. et al. Genetic regulation of human adipose microRNA expression and its consequences for metabolic traits. Hum. Mol. Genet. 22, 3023–3037 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Vohl, M. C. et al. A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men. Obes. Res. 12, 1217–1222 (2004).
  Article CAS PubMed Google Scholar
• Kloting, N. et al. MicroRNA expression in human omental and subcutaneous adipose tissue. PLoS ONE 4, e4699 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Yu, J. et al. Expression profiling of PPARγ-regulated microRNAs in human subcutaneous and visceral adipogenesis in both genders. Endocrinology 155, 2155–2165 (2014).
  Article CAS PubMed Google Scholar
• Rantalainen, M. et al. MicroRNA expression in abdominal and gluteal adipose tissue is associated with mRNA expression levels and partly genetically driven. PLoS ONE 6, e27338 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Honardoost, M., Sarookhani, M. R., Arefian, E. & Soleimani, M. Insulin resistance associated genes and miRNAs. Appl. Biochem. Biotechnol. 174, 63–80 (2014).
  Article CAS PubMed Google Scholar
• Rottiers, V. & Naar, A. M. MicroRNAs in metabolism and metabolic disorders. Nat. Rev. Mol. Cell Biol. 13, 239–250 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Wu, H. L. et al. The expression of the miR-25/93/106b family of micro-RNAs in the adipose tissue of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 99, E2754–E2761 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, Y. H. et al. miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes 62, 2278–2286 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Lorente-Cebrian, S. et al. MicroRNAs regulate human adipocyte lipolysis: effects of miR-145 are linked to TNFα. PLoS ONE 9, e86800 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Lin, Y. Y. et al. KSRP and microRNA 145 are negative regulators of lipolysis in white adipose tissue. Mol. Cell. Biol. 34, 2339–2349 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Kang, M. et al. Role of microRNA-21 in regulating 3T3-L1 adipocyte differentiation and adiponectin expression. Mol. Biol. Rep. 40, 5027–5034 (2013).
  Article CAS PubMed Google Scholar
• Shi, Z. et al. Differential expression of microRNAs in omental adipose tissue from gestational diabetes mellitus subjects reveals miR-222 as a regulator of ERα expression in estrogen-induced insulin resistance. Endocrinology 155, 1982–1990 (2014).
  Article CAS PubMed Google Scholar
• Ferland-McCollough, D., Ozanne, S. E., Siddle, K., Willis, A. E. & Bushell, M. The involvement of microRNAs in type 2 diabetes. Biochem. Soc. Trans. 38, 1565–1570 (2010).
  Article CAS PubMed Google Scholar
• Maury, E. & Brichard, S. M. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol. Cell. Endocrinol. 314, 1–16 (2010).
  Article CAS PubMed Google Scholar
• Sonkoly, E. & Pivarcsi, A. microRNAs in inflammation. Int. Rev. Immunol. 28, 535–561 (2009).
  Article CAS PubMed Google Scholar
• Ge, Q., Brichard, S., Yi, X. & Li, Q. microRNAs as a new mechanism regulating adipose tissue inflammation in obesity and as a novel therapeutic strategy in the metabolic syndrome. J. Immunol. Res. 2014, 987285 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Hulsmans, M., De Keyzer, D. & Holvoet, P. MicroRNAs regulating oxidative stress and inflammation in relation to obesity and atherosclerosis. FASEB J. 25, 2515–2527 (2011).
  Article CAS PubMed Google Scholar
• Strum, J. C. et al. MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1. Mol. Endocrinol. 23, 1876–1884 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Zhuang, G. et al. A novel regulator of macrophage activation: miR-223 in obesity-associated adipose tissue inflammation. Circulation 125, 2892–2903 (2012).
  Article CAS PubMed Google Scholar
• Shi, C. et al. IL-6 and TNFα induced obesity-related inflammatory response through transcriptional regulation of miR-146b. J. Interferon Cytokine Res. 34, 342–348 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Zhu, L. et al. MiR-335, an adipogenesis-related microRNA, is involved in adipose tissue inflammation. Cell Biochem. Biophys. 68, 283–290 (2014).
  Article CAS PubMed Google Scholar
• Kim, C. et al. TNFα -induced miR-130 resulted in adipocyte dysfunction during obesity-related inflammation. FEBS Lett. 587, 3853–3858 (2013).
  Article CAS PubMed Google Scholar
• Ge, Q., Gerard, J., Noel, L., Scroyen, I. & Brichard, S. M. MicroRNAs regulated by adiponectin as novel targets for controlling adipose tissue inflammation. Endocrinology 153, 5285–5296 (2012).
  Article CAS PubMed Google Scholar
• Subedi, A. & Park, P. H. Autocrine and paracrine modulation of microRNA-155 expression by globular adiponectin in RAW 264.7 macrophages: involvement of MAPK/NF-κB pathway. Cytokine 64, 638–641 (2013).
  Article CAS PubMed Google Scholar
• Parra, P., Serra, F. & Palou, A. Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS ONE 5, e13005 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Lefterova, M. I. & Lazar, M. A. New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107–114 (2009).
  Article CAS PubMed Google Scholar
• Oskowitz, A. Z. et al. Human multipotent stromal cells from bone marrow and microRNA: regulation of differentiation and leukemia inhibitory factor expression. Proc. Natl Acad. Sci. USA 105, 18372–18377 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mudhasani, R., Imbalzano, A. N. & Jones, S. N. An essential role for Dicer in adipocyte differentiation. J. Cell. Biochem. 110, 812–816 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• McGregor, R. A. & Choi, M. S. microRNAs in the regulation of adipogenesis and obesity. Curr. Mol. Med. 11, 304–316 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Ling, H. et al. The physiological and pathophysiological roles of adipocyte miRNAs. Biochem. Cell Biol. 91, 195–202 (2013).
  Article CAS PubMed Google Scholar
• Peng, Y. et al. MicroRNAs: Emerging roles in adipogenesis and obesity. Cell. Signal. 26, 1888–1896 (2014).
  Article CAS PubMed Google Scholar
• Alexander, R., Lodish, H. & Sun, L. MicroRNAs in adipogenesis and as therapeutic targets for obesity. Expert Opin. Ther. Targets 15, 623–636 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Son, Y. H., Ka, S., Kim, A. Y. & Kim, J. B. Regulation of adipocyte differentiation via microRNAs. Endocrinol. Metab. (Seoul) 29, 122–135 (2014).
  Article Google Scholar
• Lee, Y. S. & Dutta, A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev. 21, 1025–1030 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Sun, T., Fu, M., Bookout, A. L., Kliewer, S. A. & Mangelsdorf, D. J. MicroRNA let-7 regulates 3T3-L1 adipogenesis. Mol. Endocrinol. 23, 925–931 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Kim, Y. J., Hwang, S. J., Bae, Y. C. & Jung, J. S. MiR-21 regulates adipogenic differentiation through the modulation of TGFβ signaling in mesenchymal stem cells derived from human adipose tissue. Stem Cells 27, 3093–3102 (2009).
  CAS PubMed Google Scholar
• Huang, S. et al. Upregulation of miR-22 promotes osteogenic differentiation and inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells by repressing HDAC6 protein expression. Stem Cells Dev. 21, 2531–2540 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Karbiener, M. et al. microRNA miR-27b impairs human adipocyte differentiation and targets PPARγ. Biochem. Biophys. Res. Commun. 390, 247–251 (2009).
  Article CAS PubMed Google Scholar
• Lin, Q., Gao, Z., Alarcon, R. M., Ye, J. & Yun, Z. A role of miR-27 in the regulation of adipogenesis. FEBS J. 276, 2348–2358 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Sun, F. et al. Characterization of function and regulation of miR-24-1 and miR-31. Biochem. Biophys. Res. Commun. 380, 660–665 (2009).
  Article CAS PubMed Google Scholar
• Tang, Y. F. et al. Expression of miR-31, miR-125b-5p, and miR-326 in the adipogenic differentiation process of adipose-derived stem cells. OMICS 13, 331–336 (2009).
  Article CAS PubMed Google Scholar
• Lee, E. K. et al. miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor γ expression. Mol. Cell Biol. 31, 626–638 (2011).
  Article CAS PubMed Google Scholar
• Yang, Z. et al. MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus EID-1. Stem Cells Dev. 20, 259–267 (2011).
  Article CAS PubMed Google Scholar
• Guo, Y., Chen, Y., Zhang, Y., Chen, L. & Mo, D. Up-regulated miR-145 expression inhibits porcine preadipocytes differentiation by targeting IRS1. Int. J. Biol. Sci. 8, 1408–1417 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Liu, S., Yang, Y. & Wu, J. TNFα-induced up-regulation of miR-155 inhibits adipogenesis by down-regulating early adipogenic transcription factors. Biochem. Biophys. Res. Commun. 414, 618–624 (2011).
  Article CAS PubMed Google Scholar
• Peng, Y. et al. MiR-224 impairs adipocyte early differentiation and regulates fatty acid metabolism. Int. J. Biochem. Cell Biol. 45, 1585–1593 (2013).
  Article CAS PubMed Google Scholar
• Bork, S. et al. Adipogenic differentiation of human mesenchymal stromal cells is down-regulated by microRNA-369-5p and up-regulated by microRNA-371. J. Cell Physiol. 226, 2226–2234 (2011).
  Article CAS PubMed Google Scholar
• Kinoshita, M. et al. 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. 24, 1978–1987 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Wang, Q. et al. miR-17-92 cluster accelerates adipocyte differentiation by negatively regulating tumor-suppressor Rb2/p130. Proc. Natl Acad. Sci. USA 105, 2889–2894 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Esau, C. et al. MicroRNA-143 regulates adipocyte differentiation. J. Biol. Chem. 279, 52361–52365 (2004).
  Article CAS PubMed Google Scholar
• Chen, L. et al. MicroRNA-143 regulates adipogenesis by modulating the MAP2K5–ERK5 signaling. Sci. Rep. 4, 3819 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Karbiener, M. et al. MicroRNA-30c promotes human adipocyte differentiation and co-represses PAI-1 and ALK2. RNA Biol. 8, 850–860 (2011).
  Article CAS PubMed Google Scholar
• Zaragosi, L. E. et al. 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. 12, R64 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Kim, S. Y. et al. miR-27a is a negative regulator of adipocyte differentiation via suppressing PPARγ expression. Biochem. Biophys. Res. Commun. 392, 323–328 (2010).
  Article CAS PubMed Google Scholar
• Zhang, J. F. et al. MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix. Mol. Biol. Cell 22, 3955–3961 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Skarn, M. et al. Adipocyte differentiation of human bone marrow-derived stromal cells is modulated by microRNA-155, microRNA-221, and microRNA-222. Stem Cells Dev. 21, 873–883 (2012).
  Article CAS PubMed Google Scholar
• Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).
  Article CAS PubMed Google Scholar
• Beranger, G. E. et al. In vitro brown and “brite”/“beige” adipogenesis: human cellular models and molecular aspects. Biochim. Biophys. Acta 1831, 905–914 (2013).
  Article CAS PubMed Google Scholar
• Trajkovski, M. & Lodish, H. MicroRNA networks regulate development of brown adipocytes. Trends Endocrinol. Metab. 24, 442–450 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Karbiener, M. et al. MicroRNA-26 family is required for human adipogenesis and drives characteristics of brown adipocytes. Stem Cells 32, 1578–1590 (2014).
  Article CAS PubMed Google Scholar
• Mori, M., Nakagami, H., Rodriguez-Araujo, G., Nimura, K. & Kaneda, Y. Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, Y. et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 4, 1769 (2013).
  Article PubMed CAS Google Scholar
• Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Martinez, N. J. & Walhout, A. J. The interplay between transcription factors and microRNAs in genome-scale regulatory networks. Bioessays 31, 435–445 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Schadt, E. E. Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–223 (2009).
  Article CAS PubMed Google Scholar
• Sieberts, S. K. & Schadt, E. E. Moving toward a system genetics view of disease. Mamm. Genome 18, 389–401 (2007).
  Article PubMed PubMed Central Google Scholar
• Sato, F., Tsuchiya, S., Meltzer, S. J. & Shimizu, K. MicroRNAs and epigenetics. FEBS J. 278, 1598–1609 (2011).
  Article CAS PubMed Google Scholar
• Inui, M., Martello, G. & Piccolo, S. MicroRNA control of signal transduction. Nat. Rev. Mol. Cell Biol. 11, 252–263 (2010).
  Article CAS PubMed Google Scholar
• Hagen, J. W. & Lai, E. C. microRNA control of cell–cell signaling during development and disease. Cell Cycle 7, 2327–2332 (2008).
  Article PubMed CAS Google Scholar
• Ichimura, A., Ruike, Y., Terasawa, K. & Tsujimoto, G. miRNAs and regulation of cell signaling. FEBS J. 278, 1610–1618 (2011).
  Article CAS PubMed Google Scholar
• Herranz, H. & Cohen, S. M. MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev. 24, 1339–1344 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Gomes, C. P. et al. A review of computational tools in microRNA discovery. Front. Genet. 4, 81 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Meyer, S. U. et al. Posttranscriptional regulatory networks: from expression profiling to integrative analysis of mRNA and microRNA data. Methods Mol. Biol. 1160, 165–188 (2014).
  Article CAS PubMed Google Scholar
• Tsang, J. S., Ebert, M. S. & van Oudenaarden, A. Genome-wide dissection of microRNA functions and cotargeting networks using gene set signatures. Mol. Cell 38, 140–153 (2010).
  Article PubMed PubMed Central CAS Google Scholar
• Tsang, J., Zhu, J. & van Oudenaarden, A. MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 26, 753–767 (2007).
  Article PubMed PubMed Central CAS Google Scholar
• Chavali, S. et al. MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases. RNA 19, 1552–1562 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Kulyté, A. et al. Additive effects of miRNAs and transcription factors on CCL2 production in human white adipose tissue. Diabetes 63, 1248–1258 (2014).
  Article CAS PubMed Google Scholar
• Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 10, 126–139 (2009).
  Article CAS PubMed Google Scholar
• Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Turchinovich, A., Weiz, L., Langheinz, A. & Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011).
  Article PubMed PubMed Central CAS Google Scholar
• Mathivanan, S., Ji, H. & Simpson, R. J. Exosomes: extracellular organelles important in intercellular communication. J. Proteomics 73, 1907–1920 (2010).
  Article CAS PubMed Google Scholar
• Li, L. et al. Argonaute 2 complexes selectively protect the circulating microRNAs in cell-secreted microvesicles. PLoS ONE 7, e46957 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Huang, X. et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 14, 319 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Williams, Z. et al. Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc. Natl Acad. Sci. USA 110, 4255–4260 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Blondal, T. et al. Assessing sample and miRNA profile quality in serum and plasma or other biofluids. Methods 59, S1–S6 (2013).
  Article CAS PubMed Google Scholar
• Hu, Z. et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J. Clin. Oncol. 28, 1721–1726 (2010).
  Article PubMed Google Scholar
• Ogawa, R. et al. Adipocyte-derived microvesicles contain RNA that is transported into macrophages and might be secreted into blood circulation. Biochem. Biophys. Res. Commun. 398, 723–729 (2010).
  Article CAS PubMed Google Scholar
• Muller, G., Schneider, M., Biemer-Daub, G. & Wied, S. Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cell Signal 23, 1207–1223 (2011).
  Article CAS PubMed Google Scholar
• Wang, Y. C. et al. Circulating miR-130b mediates metabolic crosstalk between fat and muscle in overweight/obesity. Diabetologia 56, 2275–2285 (2013).
  Article CAS PubMed Google Scholar
• Deng, Z. B. et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes 58, 2498–2505 (2009).
  Article PubMed PubMed Central CAS Google Scholar
• Koeck, E. S. et al. Adipocyte exosomes induce transforming growth factor β pathway dysregulation in hepatocytes: a novel paradigm for obesity-related liver disease. J. Surg. Res. 192, 268–275 (2014).
  Article CAS PubMed Google Scholar
• Guay, C. & Regazzi, R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat. Rev. Endocrinol. 9, 513–521 (2013).
  Article CAS PubMed Google Scholar
• Rome, S. Are extracellular microRNAs involved in type 2 diabetes and related pathologies? Clin. Biochem. 46, 937–945 (2013).
  Article CAS PubMed Google Scholar
• Karolina, D. S. et al. Circulating miRNA profiles in patients with metabolic syndrome. J. Clin. Endocrinol. Metab. 97, E2271–E2276 (2012).
  Article PubMed CAS Google Scholar
• Ortega, F. J. et al. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care 37, 1375–1383 (2014).
  Article CAS PubMed Google Scholar
• Zampetaki, A. et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ. Res. 107, 810–817 (2010).
  Article CAS PubMed Google Scholar
• Ortega, F. J. et al. Targeting the circulating microRNA signature of obesity. Clin. Chem. 59, 781–792 (2013).
  Article CAS PubMed Google Scholar
• Wang, Y. T., Tsai, P. C., Liao, Y. C., Hsu, C. Y. & Juo, S. H. Circulating microRNAs have a sex-specific association with metabolic syndrome. J. Biomed. Sci. 20, 72 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Prats-Puig, A. et al. Changes in circulating microRNAs are associated with childhood obesity. J. Clin. Endocrinol. Metab. 98, E1655–E1660 (2013).
  Article CAS PubMed Google Scholar
• Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).
  Article CAS PubMed Google Scholar
• Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).
  Article CAS PubMed Google Scholar
• Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).
  Article CAS PubMed Google Scholar
• Wahid, F., Shehzad, A., Khan, T. & Kim, Y. Y. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim. Biophys. Acta 1803, 1231–1243 (2010).
  Article CAS PubMed Google Scholar
• US National Institutes of Health. ClinicalTrials.gov [online], (2014).
• van Rooij, E., Purcell, A. L. & Levin, A. A. Developing microRNA therapeutics. Circ. Res. 110, 496–507 (2012).
  Article CAS PubMed Google Scholar
• Cao, Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nat. Rev. Drug Discov. 9, 107–115 (2010).
  Article CAS PubMed Google Scholar
• Czech, M. P., Aouadi, M. & Tesz, G. J. RNAi-based therapeutic strategies for metabolic disease. Nat. Rev. Endocrinol. 7, 473–484 (2011).
  Article CAS PubMed Google Scholar
• Li, Z. & Rana, T. M. Therapeutic targeting of microRNAs: current status and future challenges. Nat. Rev. Drug Discov. 13, 622–638 (2014).
  Article CAS PubMed Google Scholar
• Xu, G. et al. Modulation of hsa-miR-26b levels following adipokine stimulation. Mol. Biol. Rep. 40, 3577–3582 (2013).
  Article CAS PubMed Google Scholar
• Chen, T. et al. MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc. Res. 83, 131–139 (2009).
  Article CAS PubMed Google Scholar
• Estep, M. et al. Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 32, 487–497 (2010).
  Article CAS PubMed Google Scholar
• Zhu, L. et al. FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes. Mol. Biol. Rep. 40, 5669–5675 (2013).
  Article CAS PubMed Google Scholar
• Hulsmans, M., Van Dooren, E., Mathieu, C. & Holvoet, P. Decrease of miR-146b-5p in monocytes during obesity is associated with loss of the anti-inflammatory but not insulin signaling action of adiponectin. PLoS ONE 7, e32794 (2012).
  Article PubMed PubMed Central CAS Google Scholar
• Huang, R. S., Hu, G. Q., Lin, B., Lin, Z. Y. & Sun, C. C. MicroRNA-155 silencing enhances inflammatory response and lipid uptake in oxidized low-density lipoprotein-stimulated human THP-1 macrophages. J. Investig. Med. 58, 961–967 (2010).
  Article CAS PubMed Google Scholar
• Urbich, C., Kuehbacher, A. & Dimmeler, S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc. Res. 79, 581–588 (2008).
  Article CAS PubMed Google Scholar
• Pritchard, C. C., Cheng, H. H. & Tewari, M. MicroRNA profiling: approaches and considerations. Nat. Rev. Genet. 13, 358–369 (2012).
  Article PubMed PubMed Central CAS Google Scholar