Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

MicroRNA-mediated regulation of glucose and lipid metabolism


In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including virtually all aspects of systemic control of metabolism. Here we focus on glucose and lipid metabolism and review current knowledge of the role of miRNAs in their systemic regulation. We survey miRNA-mediated regulation of healthy metabolism as well as the contribution of miRNAs to metabolic dysfunction in disease, particularly diabetes, obesity and liver disease. Although most miRNAs act on the tissue they are produced in, it is now well established that miRNAs can also circulate in bodily fluids, including their intercellular transport by extracellular vesicles, and we discuss the role of such extracellular miRNAs in systemic metabolic control and as potential biomarkers of metabolic status and metabolic disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Insulin synthesis and secretion in the islet β-cell and its control by miRNAs.
Fig. 2: Insulin signal transduction and metabolic responses in peripheral tissues and their control by miRNAs.
Fig. 3: HDL biogenesis and control by miRNAs in hepatocytes.
Fig. 4: Control of lipid metabolism and LDL biogenesis/turnover by miRNAs.


  1. 1.

    Carthew, R. W. & Sontheimer, E. J. Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642–655 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat. Rev. Genet. 9, 102–114 (2008).

    CAS  PubMed  Google Scholar 

  4. 4.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

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

    CAS  PubMed  Google Scholar 

  6. 6.

    Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).

    CAS  PubMed  Google Scholar 

  7. 7.

    Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F. & Hannon, G. J. Processing of primary microRNAs by the microprocessor complex. Nature 432, 231–235 (2004).

    CAS  PubMed  Google Scholar 

  8. 8.

    Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).

    CAS  PubMed  Google Scholar 

  9. 9.

    Grishok, A. et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106, 23–34 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hutvagner, G. et al. A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293, 834–838 (2001).

    CAS  PubMed  Google Scholar 

  11. 11.

    Ketting, R. F. et al. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev. 15, 2654–2659 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Meijer, H. A., Smith, E. M. & Bushell, M. Regulation of miRNA strand selection: follow the leader? Biochem. Soc. Trans. 42, 1135–1140 (2014).

    CAS  PubMed  Google Scholar 

  13. 13.

    Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    CAS  PubMed  Google Scholar 

  14. 14.

    Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Jan, C. H., Friedman, R. C., Ruby, J. G. & Bartel, D. P. Formation, regulation and evolution of Caenorhabditis elegans 3’UTRs. Nature 469, 97–101 (2011).

    CAS  PubMed  Google Scholar 

  16. 16.

    Fromm, B. et al. A uniform system for the annotation of vertebrate microRNA genes and the evolution of the human microRNAome. Annu. Rev. Genet. 49, 213–242 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Kozomara, A., Birgaoanu, M. & Griffiths-Jones, S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 47, D155–D162 (2019).

    CAS  PubMed  Google Scholar 

  18. 18.

    Fromm, B. et al. MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Res. 48, D1172 (2020).

    PubMed  Google Scholar 

  19. 19.

    Kalvari, I. et al. Rfam 13.0: shifting to a genome-centric resource for non-coding RNA families. Nucleic Acids Res. 46, D335–D342 (2018).

    CAS  PubMed  Google Scholar 

  20. 20.

    Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Lynn, F. C. Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol. Metab. 20, 452–459 (2009).

    CAS  PubMed  Google Scholar 

  22. 22.

    Guller, I. & Russell, A. P. MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J. Physiol. 588, 4075–4087 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Haeusler, R. A., McGraw, T. E. & Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol. 19, 31–44 (2018).

    CAS  PubMed  Google Scholar 

  24. 24.

    Dalgaard, L. T. & Eliasson, L. An ‘alpha-beta’ of pancreatic islet microribonucleotides. Int. J. Biochem. Cell Biol. 88, 208–219 (2017).

    CAS  PubMed  Google Scholar 

  25. 25.

    Rorsman, P. & Ashcroft, F. M. Pancreatic beta-cell electrical activity and insulin secretion: of mice and men. Physiol. Rev. 98, 117–214 (2018).

    CAS  Google Scholar 

  26. 26.

    Melloul, D., Marshak, S. & Cerasi, E. Regulation of insulin gene transcription. Diabetologia 45, 309–326 (2002).

    CAS  PubMed  Google Scholar 

  27. 27.

    Andrali, S. S., Sampley, M. L., Vanderford, N. L. & Ozcan, S. Glucose regulation of insulin gene expression in pancreatic beta-cells. Biochem. J. 415, 1–10 (2008).

    CAS  PubMed  Google Scholar 

  28. 28.

    Rorsman, P. et al. The cell physiology of biphasic insulin secretion. New Physiol. Sci. 15, 72–77 (2000).

    CAS  Google Scholar 

  29. 29.

    Wang, Z. & Thurmond, D. C. Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins. J. Cell Sci. 122, 893–903 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Arous, C. & Halban, P. A. The skeleton in the closet: actin cytoskeletal remodeling in beta-cell function. Am. J. Physiol. Endocrinol. Metab. 309, E611–E620 (2015).

    CAS  PubMed  Google Scholar 

  31. 31.

    Ofori, J. K. et al. Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell. Sci. Rep. 7, 44986 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Li, X., Cassidy, J. J., Reinke, C. A., Fischboeck, S. & Carthew, R. W. A microRNA imparts robustness against environmental fluctuation during development. Cell 137, 273–282 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Wienholds, E. et al. MicroRNA expression in zebrafish embryonic development. Science 309, 310–311 (2005).

    CAS  PubMed  Google Scholar 

  34. 34.

    Correa-Medina, M. et al. MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. Gene Expr. Patterns 9, 193–199 (2008).

    PubMed  Google Scholar 

  35. 35.

    Christodoulou, F. et al. Ancient animal microRNAs and the evolution of tissue identity. Nature 463, 1084–1088 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kredo-Russo, S. et al. Pancreas-enriched miRNA refines endocrine cell differentiation. Development 139, 3021–3031 (2012).

    CAS  PubMed  Google Scholar 

  37. 37.

    Agbu, P., Cassidy, J. J., Braverman, J., Jacobson, A. & Carthew, R. W. MicroRNA miR-7 regulates secretion of insulin-like peptides. Endocrinology 161, bqz040 (2020). This article shows that miR-7-mediated regulation of insulin secretion is deeply conserved and suggests that the ancestor of invertebrates and vertebrates used this miRNA to regulate glucose metabolism.

    PubMed  Google Scholar 

  38. 38.

    Melkman-Zehavi, T. et al. miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J. 30, 835–845 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sebastiani, G. et al. MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetol. 52, 523–530 (2015).

    CAS  PubMed  Google Scholar 

  40. 40.

    Zhang, F. et al. Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion. Nat. Commun. 11, 1822 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tang, X., Muniappan, L., Tang, G. & Ozcan, S. Identification of glucose-regulated miRNAs from pancreatic beta cells reveals a role for miR-30d in insulin transcription. RNA 15, 287–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Yang, L. et al. EGF suppresses the expression of miR-124a in pancreatic beta cell lines via ETS2 activation through the MEK and PI3K signaling pathways. Int. J. Biol. Sci. 15, 2561–2575 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Xu, H. et al. Pancreatic beta cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving beta cell function. PLoS Biol. 18, e3000603 (2020). This article describes a miRNA from pancreatic islet cells that not only regulates insulin output autonomously but also circulates in the blood and sensitizes target tissues to respond to insulin, and therefore could be a potential therapeutic.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Latreille, M. et al. MicroRNA-7a regulates pancreatic beta cell function. J. Clin. Invest. 124, 2722–2735 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Caldwell, J. E., Heiss, S. G., Mermall, V. & Cooper, J. A. Effects of CapZ, an actin capping protein of muscle, on the polymerization of actin. Biochemistry 28, 8506–8514 (1989).

    CAS  PubMed  Google Scholar 

  46. 46.

    Delalle, I., Pfleger, C. M., Buff, E., Lueras, P. & Hariharan, I. K. Mutations in the Drosophila orthologs of the F-actin capping protein alpha- and beta-subunits cause actin accumulation and subsequent retinal degeneration. Genetics 171, 1757–1765 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004). This article describes miR-375 and its role in regulating insulin secretion.

    CAS  PubMed  Google Scholar 

  48. 48.

    Taoka, M. et al. V-1, a protein expressed transiently during murine cerebellar development, regulates actin polymerization via interaction with capping protein. J. Biol. Chem. 278, 5864–5870 (2003).

    CAS  PubMed  Google Scholar 

  49. 49.

    Bhattacharya, N., Ghosh, S., Sept, D. & Cooper, J. A. Binding of myotrophin/V-1 to actin-capping protein: implications for how capping protein binds to the filament barbed end. J. Biol. Chem. 281, 31021–31030 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Quintens, R., Hendrickx, N., Lemaire, K. & Schuit, F. Why expression of some genes is disallowed in beta-cells. Biochem. Soc. Trans. 36, 300–305 (2008).

    CAS  PubMed  Google Scholar 

  51. 51.

    Zhao, C., Wilson, M. C., Schuit, F., Halestrap, A. P. & Rutter, G. A. Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50, 361–366 (2001).

    CAS  PubMed  Google Scholar 

  52. 52.

    Pullen, T. J., da Silva Xavier, G., Kelsey, G. & Rutter, G. A. miR-29a and miR-29b contribute to pancreatic beta-cell-specific silencing of monocarboxylate transporter 1 (MCT1). Mol. Cell Biol. 31, 3182–3194 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Brubaker, P. L. & Drucker, D. J. Minireview: glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 145, 2653–2659 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Jo, S. et al. miR-204 controls glucagon-like peptide 1 receptor expression and agonist function. Diabetes 67, 256–264 (2018).

    CAS  PubMed  Google Scholar 

  55. 55.

    Szabo, G. & Bala, S. MicroRNAs in liver disease. Nat. Rev. Gastroenterol. Hepatol. 10, 542–552 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Davalos, A. et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc. Natl Acad. Sci. USA 108, 9232–9237 (2011).

    CAS  PubMed  Google Scholar 

  57. 57.

    Liu, W. et al. Hepatic miR-378 targets p110alpha and controls glucose and lipid homeostasis by modulating hepatic insulin signalling. Nat. Commun. 5, 5684 (2014).

    CAS  PubMed  Google Scholar 

  58. 58.

    Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Williams, A. H., Liu, N., van Rooij, E. & Olson, E. N. MicroRNA control of muscle development and disease. Curr. Opin. Cell Biol. 21, 461–469 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zhu, H. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Dou, L. et al. MiR-19a regulates PTEN expression to mediate glycogen synthesis in hepatocytes. Sci. Rep. 5, 11602 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Ramirez, C. M. et al. MicroRNA 33 regulates glucose metabolism. Mol. Cell Biol. 33, 2891–2902 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chemello, F. et al. Transcriptomic analysis of single isolated myofibers identifies miR-27a-3p and miR-142-3p as regulators of metabolism in skeletal muscle. Cell Rep. 26, 3784–3797 e3788 (2019).

    CAS  PubMed  Google Scholar 

  64. 64.

    Liang, J. et al. MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis. J. Hepatol. 58, 535–542 (2013).

    CAS  PubMed  Google Scholar 

  65. 65.

    Zhuo, S. et al. MicroRNA-451 negatively regulates hepatic glucose production and glucose homeostasis by targeting glycerol kinase-mediated gluconeogenesis. Diabetes 65, 3276–3288 (2016).

    CAS  PubMed  Google Scholar 

  66. 66.

    Wang, S. et al. Micro-RNA-27a/b negatively regulates hepatic gluconeogenesis by targeting FOXO1. Am. J. Physiol. Endocrinol. Metab. 317, E911–E924 (2019).

    CAS  PubMed  Google Scholar 

  67. 67.

    Gerin, I. et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J. Biol. Chem. 285, 33652–33661 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997).

    CAS  PubMed  Google Scholar 

  69. 69.

    Espenshade, P. J. & Hughes, A. L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401–427 (2007).

    CAS  PubMed  Google Scholar 

  70. 70.

    Foretz, M., Guichard, C., Ferre, P. & Foufelle, F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc. Natl Acad. Sci. USA 96, 12737–12742 (1999).

    CAS  PubMed  Google Scholar 

  71. 71.

    Yamamoto, T. et al. SREBP-1 interacts with hepatocyte nuclear factor-4 alpha and interferes with PGC-1 recruitment to suppress hepatic gluconeogenic genes. J. Biol. Chem. 279, 12027–12035 (2004).

    CAS  PubMed  Google Scholar 

  72. 72.

    Wu, L. et al. Paternal psychological stress reprograms hepatic gluconeogenesis in offspring. Cell Metab. 23, 735–743 (2016). This article shows that transgenerational epigenetic transmission of a glucose metabolic state is mediated by a miRNA.

    CAS  PubMed  Google Scholar 

  73. 73.

    Bluher, M. Obesity: global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 15, 288–298 (2019).

    PubMed  Google Scholar 

  74. 74.

    Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Price, N. L. et al. Genetic ablation of miR-33 increases food intake, enhances adipose tissue expansion, and promotes obesity and insulin resistance. Cell Rep. 22, 2133–2145 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Swallow, D. M. Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet. 37, 197–219 (2003).

    CAS  PubMed  Google Scholar 

  77. 77.

    Kettunen, J. et al. European lactase persistence genotype shows evidence of association with increase in body mass index. Hum. Mol. Genet. 19, 1129–1136 (2010).

    CAS  PubMed  Google Scholar 

  78. 78.

    Field, Y. et al. Detection of human adaptation during the past 2000 years. Science 354, 760–764 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Bovine HapMap, C. et al. Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds. Science 324, 528–532 (2009).

    Google Scholar 

  80. 80.

    Wagschal, A. et al. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat. Med. 21, 1290–1297 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Plassais, J. et al. Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology. Nat. Commun. 10, 1489 (2019).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Wang, W. X., Wilfred, B. R., Hu, Y., Stromberg, A. J. & Nelson, P. T. Anti-Argonaute RIP-Chip shows that miRNA transfections alter global patterns of mRNA recruitment to microribonucleoprotein complexes. RNA 16, 394–404 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Wang, L. et al. A microRNA linking human positive selection and metabolic disorders. Cell 183, 684–701 e614 (2020). This article shows how a miRNA gene variant co-selected in humans confers energy efficiency that predisposes humans and mice to obesity.

    CAS  PubMed  Google Scholar 

  84. 84.

    Yang, W. M., Jeong, H. J., Park, S. W. & Lee, W. Obesity-induced miR-15b is linked causally to the development of insulin resistance through the repression of the insulin receptor in hepatocytes. Mol. Nutr. Food Res. 59, 2303–2314 (2015).

    CAS  PubMed  Google Scholar 

  85. 85.

    Jordan, S. D. et al. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat. Cell Biol. 13, 434–446 (2011).

    CAS  PubMed  Google Scholar 

  86. 86.

    Kornfeld, J. W. et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of HNF1B. Nature 494, 111–115 (2013).

    CAS  PubMed  Google Scholar 

  87. 87.

    Zhang, C. et al. Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology. Nat. Commun. 9, 3658 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  PubMed  Google Scholar 

  89. 89.

    Kameswaran, V. et al. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab. 19, 135–145 (2014).

    CAS  PubMed  Google Scholar 

  90. 90.

    Locke, J. M., da Silva Xavier, G., Dawe, H. R., Rutter, G. A. & Harries, L. W. Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion. Diabetologia 57, 122–128 (2014).

    CAS  PubMed  Google Scholar 

  91. 91.

    Jin, T. The WNT signalling pathway and diabetes mellitus. Diabetologia 51, 1771–1780 (2008).

    CAS  PubMed  Google Scholar 

  92. 92.

    Belgardt, B. F. et al. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat. Med. 21, 619–627 (2015).

    CAS  PubMed  Google Scholar 

  93. 93.

    Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Chinetti, G. et al. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med. 7, 53–58 (2001).

    CAS  PubMed  Google Scholar 

  95. 95.

    Tall, A. R., Yvan-Charvet, L., Terasaka, N., Pagler, T. & Wang, N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 7, 365–375 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Horie, T. et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (SREBP2) regulates HDL in vivo. Proc. Natl Acad. Sci. USA 107, 17321–17326 (2010).

    CAS  PubMed  Google Scholar 

  97. 97.

    Marquart, T. J., Allen, R. M., Ory, D. S. & Baldan, A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc. Natl Acad. Sci. USA 107, 12228–12232 (2010).

    CAS  PubMed  Google Scholar 

  98. 98.

    Najafi-Shoushtari, S. H. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328, 1566–1569 (2010).

    CAS  PubMed  Google Scholar 

  99. 99.

    Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Adlakha, Y. K. et al. Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRalpha expression and cholesterol homeostasis. Cell Death Dis. 4, e780 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Ramirez, C. M. et al. Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ. Res. 112, 1592–1601 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    de Aguiar Vallim, T. Q. et al. MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ. Res. 112, 1602–1612 (2013).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Goedeke, L. et al. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat. Med. 21, 1280–1289 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Rayner, K. J. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404–407 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Rayner, K. J. et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J. Clin. Invest. 121, 2921–2931 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Price, N. L. et al. Specific disruption of ABCA1 targeting largely mimics the effects of miR-33 knockout on macrophage cholesterol efflux and atherosclerotic plaque development. Circ. Res. 124, 874–880 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Rottiers, V. et al. MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb. Symp. Quant. Biol. 76, 225–233 (2011).

    CAS  PubMed  Google Scholar 

  108. 108.

    Allen, R. M. et al. miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity. EMBO Mol. Med. 4, 882–895 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Li, T., Francl, J. M., Boehme, S. & Chiang, J. Y. Regulation of cholesterol and bile acid homeostasis by the cholesterol 7alpha-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice. Hepatology 58, 1111–1121 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Goedeke, L. et al. A regulatory role for microRNA 33* in controlling lipid metabolism gene expression. Mol. Cell Biol. 33, 2339–2352 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Soh, J., Iqbal, J., Queiroz, J., Fernandez-Hernando, C. & Hussain, M. M. MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat. Med. 19, 892–900 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Chang, J. et al. miR-122, a mammalian liver-specific microRNA, is processed from HCR mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 1, 106–113 (2004).

    CAS  PubMed  Google Scholar 

  113. 113.

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

    PubMed  Google Scholar 

  114. 114.

    Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).

    CAS  PubMed  Google Scholar 

  115. 115.

    Elmen, J. et al. Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 36, 1153–1162 (2008).

    CAS  PubMed  Google Scholar 

  116. 116.

    Vickers, K. C. et al. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology 57, 533–542 (2013).

    CAS  PubMed  Google Scholar 

  117. 117.

    Zhang, M., Sun, W., Zhou, M. & Tang, Y. MicroRNA-27a regulates hepatic lipid metabolism and alleviates NAFLD via repressing FAS and SCD1. Sci. Rep. 7, 14493 (2017).

    PubMed  PubMed Central  Google Scholar 

  118. 118.

    Vickers, K. C. et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc. Natl Acad. Sci. USA 111, 14518–14523 (2014).

    CAS  PubMed  Google Scholar 

  119. 119.

    Wang, L. et al. MicroRNAs 185, 96, and 223 repress selective high-density lipoprotein cholesterol uptake through posttranscriptional inhibition. Mol. Cell Biol. 33, 1956–1964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Xu, Y. et al. A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism. Nat. Commun. 6, 7466 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Singaravelu, R. et al. MicroRNA-7 mediates cross-talk between metabolic signaling pathways in the liver. Sci. Rep. 8, 361 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Breslow, J. L. Mouse models of atherosclerosis. Science 272, 685–688 (1996).

    CAS  PubMed  Google Scholar 

  123. 123.

    Masucci-Magoulas, L. et al. A mouse model with features of familial combined hyperlipidemia. Science 275, 391–394 (1997).

    CAS  PubMed  Google Scholar 

  124. 124.

    Horie, T. et al. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J. Am. Heart Assoc. 1, e003376 (2012).

    PubMed  PubMed Central  Google Scholar 

  125. 125.

    Price, N. L. et al. Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis. Cell Rep. 21, 1317–1330 (2017). This article points out the potential use of anti-miR-33 for reducing the progression of atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Ouimet, M. et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J. Clin. Invest. 125, 4334–4348 (2015).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Cheng, J. et al. MicroRNA-144 silencing protects against atherosclerosis in male, but not female mice. Arterioscler. Thromb. Vasc. Biol. 40, 412–425 (2020).

    CAS  PubMed  Google Scholar 

  128. 128.

    Irani, S., Iqbal, J., Antoni, W. J., Ijaz, L. & Hussain, M. M. microRNA-30c reduces plasma cholesterol in homozygous familial hypercholesterolemic and type 2 diabetic mouse models. J. Lipid Res. 59, 144–154 (2018).

    CAS  PubMed  Google Scholar 

  129. 129.

    Wan, Y. et al. Regulation of cellular senescence by miR-34a in alcoholic liver injury. Am. J. Pathol. 187, 2788–2798 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Ding, J. et al. Effect of miR-34a in regulating steatosis by targeting PPARalpha expression in nonalcoholic fatty liver disease. Sci. Rep. 5, 13729 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Satishchandran, A. et al. MicroRNA 122, regulated by GRLH2, protects livers of mice and patients from ethanol-induced liver disease. Gastroenterology 154, 238–252 e237 (2018). This article demonstrates that the abundant miR-122 is downregulated by alcohol-induced liver disease, and that its artificial expression can protect the liver from disease progression.

    CAS  PubMed  Google Scholar 

  132. 132.

    van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).

    PubMed  Google Scholar 

  133. 133.

    Gibbings, D. J., Ciaudo, C., Erhardt, M. & Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11, 1143–1149 (2009).

    CAS  PubMed  Google Scholar 

  134. 134.

    Lee, Y. S. et al. Silencing by small RNAs is linked to endosomal trafficking. Nat. Cell Biol. 11, 1150–1156 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Mori, M. A., Ludwig, R. G., Garcia-Martin, R., Brandao, B. B. & Kahn, C. R. Extracellular miRNAs: from biomarkers to mediators of physiology and disease. Cell Metab. 30, 656–673 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).

    CAS  PubMed  Google Scholar 

  137. 137.

    Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Mori, M. A. et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J. Clin. Invest. 124, 3339–3351 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Thomou, T. et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542, 450–455 (2017). This article shows that adipose tissue secretes extracellular vesicles loaded with miRNAs into the circulation, and this can promote insulin sensitivity in target tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Brandao, B. B. et al. Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise. Proc. Natl Acad. Sci. USA 117, 23932–23941 (2020).

    CAS  PubMed  Google Scholar 

  141. 141.

    Ying, W. et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell 171, 372–384 e312 (2017). This article shows that a major source of circulating miRNAs is adipose tissue, and that circulating miRNAs from obese mice injected into lean mice cause insulin resistance, and vice versa.

    CAS  PubMed  Google Scholar 

  142. 142.

    Castano, C., Kalko, S., Novials, A. & Parrizas, M. Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc. Natl Acad. Sci. USA 115, 12158–12163 (2018). This article shows that circulating miRNAs from obese mice injected into lean mice cause insulin resistance, and that synthetic extracellular vesicles loaded with miRNAs misexpressed in obesity can mimic the effect.

    CAS  PubMed  Google Scholar 

  143. 143.

    Guay, C., Menoud, V., Rome, S. & Regazzi, R. Horizontal transfer of exosomal microRNAs transduce apoptotic signals between pancreatic beta-cells. Cell Commun. Signal. 13, 17 (2015).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D. & Remaley, A. T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Sedgeman, L. R. et al. Beta cell secretion of miR-375 to HDL is inversely associated with insulin secretion. Sci. Rep. 9, 3803 (2019).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Oses, M., Margareto Sanchez, J., Portillo, M. P., Aguilera, C. M. & Labayen, I. Circulating miRNAs as biomarkers of obesity and obesity-associated comorbidities in children and adolescents: a systematic review. Nutrients 11, 2890 (2019).

    PubMed Central  Google Scholar 

  147. 147.

    Kamalden, T. A. et al. Exosomal microRNA-15a transfer from the pancreas augments diabetic complications by inducing oxidative stress. Antioxid. Redox Signal. 27, 913–930 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Sangalli, E. et al. Circulating microRNA-15a associates with retinal damage in patients with early stage type 2 diabetes. Front. Endocrinol. 11, 254 (2020).

    Google Scholar 

  149. 149.

    Katayama, M. et al. Circulating exosomal miR-20b-5p is elevated in type 2 diabetes and could impair insulin action in human skeletal muscle. Diabetes 68, 515–526 (2019).

    CAS  PubMed  Google Scholar 

  150. 150.

    Buchanan, T. A. & Xiang, A. H. Gestational diabetes mellitus. J. Clin. Invest. 115, 485–491 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Yoffe, L. et al. Early diagnosis of gestational diabetes mellitus using circulating microRNAs. Eur. J. Endocrinol. 181, 565–577 (2019).

    PubMed  Google Scholar 

  152. 152.

    Ebert, M. S. & Sharp, P. A. Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Doyle, J. C., Francis, B. A. & Tannenbaum, A. R. Feedback Control Theory (Courier Corporation, 2013).

  154. 154.

    Cassidy, J. J. et al. Repressive gene regulation synchronizes development with cellular metabolism. Cell 178, 980–992 e917 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


The authors apologize to those whose work they omitted in this Review due to space limitations. They thank the following funding agencies for support: NIH (T32GM008061 and R35GM118144), NSF (1764421) and the Simons Foundation (597491).

Author information




The authors contributed equally to all aspects of the original manuscript, and R.W.C made all revisions to the manuscript.

Corresponding author

Correspondence to Richard W. Carthew.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks C. Fernandez-Hernando, R. Kahn and L. Eliasson for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Argonaute (Ago) family

A class of proteins conserved in eukaryotes that associate with small RNAs such as PIWI-interacting RNAs, microRNAs and siRNAs, and together the RNA–induced silencing complex acts upon DNA or RNA targets.

Seed sequence

A heptamer sequence located at nucleotides 2–7 relative to the 5′ end of a microRNA. The seed sequence is essential for binding of the microRNA in the RNA-induced silencing complex to a target mRNA, with the binding site typically located in the 3′ untranslated region.

Bilateral animals

Animals with bilateral symmetry as an embryo. Bilateral symmetry is where the body has a left side and a right side that are mirror images of one another. Animals that do not fall into this category include sponges, ctenophores, placozoans and cnidarians.

Islets of Langerhans

Regions of the pancreas that contain endocrine cells responsible for glucose homeostasis. Constituting 1–2% of the pancreas volume, there are approximately one million islets distributed throughout the pancreas in density routes.


Eukaryotic protein family that mediates the fusion of membrane-bound vesicles with a target membrane. Target membranes can include the plasma membrane (exocytosis) and membrane-bound compartments such as the Golgi apparatus.

Insulin-like peptides

The evolutionarily ancient superfamily of peptides that include insulin, insulin-like growth factors and peptides within the invertebrates that fulfil functions homologous to those of vertebrate insulin and insulin-like growth factors.

Barbed ends of F-actin

Actin filaments have polarity, with each filament having a barbed end and a pointed end. Actin monomers are added to filaments predominantly at the barbed end, whereas release of monomers from a filament occurs predominantly at the pointed end. In the cell, filaments are continuously turned over by dynamic monomer–filament exchange.

Incretin hormone

Incretins are peptides secreted into the circulatory system by specialized enteroendocrine cells in the gut upon nutrient ingestion and absorption. They target the islets of Langerhans, where they augment the response of β-cells to glucose by secreting insulin.

Insulin resistance

A condition where cells of the liver, fat and muscle are not as responsive to insulin doses that elicit normal responses in healthy individuals. Consequently, cells do not absorb glucose from the blood as readily, and the pancreas responds by secreting even more insulin to overcome the weak response to insulin.


Lipoproteins carry cholesterol and triglycerides in the circulation, and they can both deliver and remove lipids from cells to mediate lipid homeostasis. Lipoproteins do not simply associate with lipids into small molecular complexes, but rather are found as lipoprotein particles of various sizes in the blood plasma.

PPAR transcription factors

A family of nuclear receptor proteins that control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. Endogenous ligands for peroxisome proliferator-activated receptors (PPARs) include free fatty acids, eicosanoids and vitamin B3.


Proteins that bind to lipids and form lipoproteins, which circulate in the blood, lymph and cerebrospinal fluid. They not only function to solubilize lipids for transport but also interact with lipoprotein receptors and lipid transport proteins to facilitate lipoprotein uptake and clearance.


A small synthetic RNA whose purpose is to block the action of a specific microRNA in vivo. An antagomir is fully complementary to a microRNA except for a mismatch or chemical modification at the site of RNA-induced silencing complex cleavage, so as to prevent the antagomir from being cleaved. Antagomirs often have other chemical modifications to inhibit their degradation by ribonucleases.


A member of the fibroblast growth factor family. It is secreted from liver cells into the circulatory system. It binds to a receptor on the surface of cells of the hypothalamus and regulates simple sugar intake and preference for sweet foods.


Also known as adipocytokines, these molecules are cytokines that are secreted by adipose tissue. Representative adipokines include leptin, IL-6 and TNF.


A member of the protein kinase C (PKC) family, which phosphorylate target proteins at serine and threonine residues. Kinase activation requires a second messenger, and this PKC isoform requires binding to diacylglycerol. It does not require binding to calcium, and thus it is a member of the novel subfamily of PKCs.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Agbu, P., Carthew, R.W. MicroRNA-mediated regulation of glucose and lipid metabolism. Nat Rev Mol Cell Biol 22, 425–438 (2021).

Download citation


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing