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MicroRNA regulatory networks in human adipose tissue and obesity

Nature Reviews Endocrinology volume 11, pages 276–288 (2015)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) are important for fat cell formation (adipogenesis) and for regulating the metabolic and endocrine functions of these cells

  • Obesity influences the expression of miRNAs in adipose tissue, but altered expression of only a few of these miRNAs has been experimentally verified in humans

  • Regional variations in expression of miRNAs in human adipose tissues have been demonstrated

  • miRNAs signal through complex networks involving transcription factors, which has been demonstrated in the context of regulation of inflammation in human adipose tissue

  • Extracellular miRNAs have specific expression profiles in obesity

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and, therefore, biological processes in different tissues. A major function of miRNAs in adipose tissue is to stimulate or inhibit the differentiation of adipocytes, and to regulate specific metabolic and endocrine functions. Numerous miRNAs are present in human adipose tissue; however, the expression of only a few is altered in individuals with obesity and type 2 diabetes mellitus or are differentially expressed in various adipose depots. In humans, obesity is associated with chronic low-grade inflammation that is regulated by signal transduction networks, in which miRNAs, either directly or indirectly (through regulatory elements such as transcription factors), influence the expression and secretion of inflammatory proteins. In addition to their diverse effects on signalling, miRNAs and transcription factors can interact to amplify the inflammatory effect. Although additional miRNA signal networks in human adipose tissue are not yet known, similar regulatory circuits have been described in brown adipose tissue in mice. miRNAs can also be secreted from fat cells into the circulation and serve as markers of disturbed adipose tissue function. Given their role in regulating transcriptional networks, miRNAs in adipose tissue might offer tangible targets for treating metabolic disorders.

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Figure 1: miRNAs and verified targets that contribute to adipogenesis in humans.
Figure 2: miRNA signalling in adipose tissue.
Figure 3: Experimental pipeline implemented to elucidate integrative miRNA–gene regulatory networks in human adipose tissues.
Figure 4: miRNA regulatory circuits that control levels of CCL2 in human white adipose tissue.

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References

  1. Haslam, D. W. & James, W. P. Obesity. Lancet 366, 1197–1209 (2005).

    Article  PubMed  Google Scholar 

  2. 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 

  3. Prentice, A. M. The emerging epidemic of obesity in developing countries. Int. J. Epidemiol. 35, 93–99 (2006).

    Article  PubMed  Google Scholar 

  4. Bray, G. A. & Tartaglia, L. A. Medicinal strategies in the treatment of obesity. Nature 404, 672–677 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Arner, E. & Arner, P. Health and obesity: not just skin deep. Science 342, 558–559 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Arner, P. Not all fat is alike. Lancet 351, 1301–1302 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Johnson, A. M. & Olefsky, J. M. The origins and drivers of insulin resistance. Cell 152, 673–684 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Turer, A. T. & Scherer, P. E. Adiponectin: mechanistic insights and clinical implications. Diabetologia 55, 2319–2326 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    CAS  PubMed  Google Scholar 

  12. Rosen, E. D. & Spiegelman, B. M. Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16, 145–171 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. 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 

  15. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Nuutila, P. Brown adipose tissue thermogenesis in humans. Diabetologia 56, 2110–2112 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

  25. 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 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. Kuhn, D. E. et al. Experimental validation of miRNA targets. Methods 44, 47–54 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 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 

  32. 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 

  33. 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 

  34. 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 

  35. Martinelli, R. et al. miR-519d overexpression is associated with human obesity. Obesity (Silver Spring) 18, 2170–2176 (2010).

    Article  CAS  Google Scholar 

  36. 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 

  37. 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 

  38. 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 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. 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 

  52. 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 

  53. 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 

  54. 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 

  55. 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 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. 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 

  62. Sonkoly, E. & Pivarcsi, A. microRNAs in inflammation. Int. Rev. Immunol. 28, 535–561 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. 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 

  65. 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 

  66. 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 

  67. 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 

  68. 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 

  69. 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 

  70. 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 

  71. 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 

  72. 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 

  73. Lefterova, M. I. & Lazar, M. A. New developments in adipogenesis. Trends Endocrinol. Metab. 20, 107–114 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. 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 

  76. 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 

  77. Ling, H. et al. The physiological and pathophysiological roles of adipocyte miRNAs. Biochem. Cell Biol. 91, 195–202 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Peng, Y. et al. MicroRNAs: Emerging roles in adipogenesis and obesity. Cell. Signal. 26, 1888–1896 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. 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 

  81. 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 

  82. 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 

  83. 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 

  84. 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 

  85. 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 

  86. 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 

  87. 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 

  88. 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 

  89. 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 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. 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 

  95. 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 

  96. 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 

  97. Esau, C. et al. MicroRNA-143 regulates adipocyte differentiation. J. Biol. Chem. 279, 52361–52365 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. 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 

  99. 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 

  100. 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 

  101. 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 

  102. 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 

  103. 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 

  104. Peirce, V., Carobbio, S. & Vidal-Puig, A. The different shades of fat. Nature 510, 76–83 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. 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 

  106. 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 

  107. 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 

  108. 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 

  109. 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 

  110. Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. 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 

  112. Schadt, E. E. Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–223 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. 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 

  114. Sato, F., Tsuchiya, S., Meltzer, S. J. & Shimizu, K. MicroRNAs and epigenetics. FEBS J. 278, 1598–1609 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. 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 

  116. 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 

  117. 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 

  118. 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 

  119. 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 

  120. 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 

  121. 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 

  122. 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 

  123. 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 

  124. 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 

  125. 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 

  126. 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 

  127. 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 

  128. 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 

  129. 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 

  130. 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 

  131. 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 

  132. 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 

  133. 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 

  134. 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 

  135. 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 

  136. 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 

  137. 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 

  138. 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 

  139. Guay, C. & Regazzi, R. Circulating microRNAs as novel biomarkers for diabetes mellitus. Nat. Rev. Endocrinol. 9, 513–521 (2013).

    Article  CAS  PubMed  Google Scholar 

  140. Rome, S. Are extracellular microRNAs involved in type 2 diabetes and related pathologies? Clin. Biochem. 46, 937–945 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. 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 

  142. 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 

  143. 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 

  144. Ortega, F. J. et al. Targeting the circulating microRNA signature of obesity. Clin. Chem. 59, 781–792 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. 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 

  146. 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 

  147. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature 438, 685–689 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. 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 

  149. Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates. Nature 452, 896–899 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. 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 

  151. US National Institutes of Health. ClinicalTrials.gov [online], (2014).

  152. van Rooij, E., Purcell, A. L. & Levin, A. A. Developing microRNA therapeutics. Circ. Res. 110, 496–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. 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 

  154. 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 

  155. 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 

  156. 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 

  157. 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 

  158. 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 

  159. 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 

  160. 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 

  161. 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 

  162. 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 

  163. 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 

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Acknowledgements

P.A. has received funding from the Swedish Research Council, the Swedish Diabetes Foundation and the Diabetes Program at Karolinska Institutet. A.K. has received funding from the Åke Wiberg Foundation and Tore Nilsson Foundation.

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  1. Department of Medicine Huddinge, Lipid Laboratory, Karolinska Institutet, Stockholm, SE-141 86, Sweden

    Peter Arner & Agné Kulyté

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  1. Peter Arner
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P.A. and A.K. contributed equally to all aspects of the article.

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Correspondence to Peter Arner.

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P.A. has received funding from the Novo Nordisk Foundation, which is a non-profit organization fully independent of the pharmaceutical company Novo Nordisk Ltd. A.K. declares no competing interests.

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Arner, P., Kulyté, A. MicroRNA regulatory networks in human adipose tissue and obesity. Nat Rev Endocrinol 11, 276–288 (2015). https://doi.org/10.1038/nrendo.2015.25

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