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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Carthew, R. W. & Sontheimer, E. J. Origins and mechanisms of miRNAs and siRNAs. Cell 136, 642–655 (2009).
Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).
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).
Baek, D. et al. The impact of microRNAs on protein output. Nature 455, 64–71 (2008).
Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).
Lee, Y. et al. The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415–419 (2003).
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).
Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004).
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).
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).
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).
Meijer, H. A., Smith, E. M. & Bushell, M. Regulation of miRNA strand selection: follow the leader? Biochem. Soc. Trans. 42, 1135–1140 (2014).
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).
Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).
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).
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).
Kozomara, A., Birgaoanu, M. & Griffiths-Jones, S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 47, D155–D162 (2019).
Fromm, B. et al. MirGeneDB 2.0: the metazoan microRNA complement. Nucleic Acids Res. 48, D1172 (2020).
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).
Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018).
Lynn, F. C. Meta-regulation: microRNA regulation of glucose and lipid metabolism. Trends Endocrinol. Metab. 20, 452–459 (2009).
Guller, I. & Russell, A. P. MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J. Physiol. 588, 4075–4087 (2010).
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).
Dalgaard, L. T. & Eliasson, L. An ‘alpha-beta’ of pancreatic islet microribonucleotides. Int. J. Biochem. Cell Biol. 88, 208–219 (2017).
Rorsman, P. & Ashcroft, F. M. Pancreatic beta-cell electrical activity and insulin secretion: of mice and men. Physiol. Rev. 98, 117–214 (2018).
Melloul, D., Marshak, S. & Cerasi, E. Regulation of insulin gene transcription. Diabetologia 45, 309–326 (2002).
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).
Rorsman, P. et al. The cell physiology of biphasic insulin secretion. New Physiol. Sci. 15, 72–77 (2000).
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).
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).
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).
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).
Wienholds, E. et al. MicroRNA expression in zebrafish embryonic development. Science 309, 310–311 (2005).
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).
Christodoulou, F. et al. Ancient animal microRNAs and the evolution of tissue identity. Nature 463, 1084–1088 (2010).
Kredo-Russo, S. et al. Pancreas-enriched miRNA refines endocrine cell differentiation. Development 139, 3021–3031 (2012).
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.
Melkman-Zehavi, T. et al. miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J. 30, 835–845 (2011).
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).
Zhang, F. et al. Obesity-induced overexpression of miR-802 impairs insulin transcription and secretion. Nat. Commun. 11, 1822 (2020).
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).
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).
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.
Latreille, M. et al. MicroRNA-7a regulates pancreatic beta cell function. J. Clin. Invest. 124, 2722–2735 (2014).
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).
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).
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.
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).
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).
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).
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).
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).
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).
Jo, S. et al. miR-204 controls glucagon-like peptide 1 receptor expression and agonist function. Diabetes 67, 256–264 (2018).
Szabo, G. & Bala, S. MicroRNAs in liver disease. Nat. Rev. Gastroenterol. Hepatol. 10, 542–552 (2013).
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).
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).
Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
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).
Zhu, H. et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81–94 (2011).
Dou, L. et al. MiR-19a regulates PTEN expression to mediate glycogen synthesis in hepatocytes. Sci. Rep. 5, 11602 (2015).
Ramirez, C. M. et al. MicroRNA 33 regulates glucose metabolism. Mol. Cell Biol. 33, 2891–2902 (2013).
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).
Liang, J. et al. MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis. J. Hepatol. 58, 535–542 (2013).
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).
Wang, S. et al. Micro-RNA-27a/b negatively regulates hepatic gluconeogenesis by targeting FOXO1. Am. J. Physiol. Endocrinol. Metab. 317, E911–E924 (2019).
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).
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).
Espenshade, P. J. & Hughes, A. L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet. 41, 401–427 (2007).
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).
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).
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.
Bluher, M. Obesity: global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 15, 288–298 (2019).
Kahn, B. B. & Flier, J. S. Obesity and insulin resistance. J. Clin. Invest. 106, 473–481 (2000).
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).
Swallow, D. M. Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet. 37, 197–219 (2003).
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).
Field, Y. et al. Detection of human adaptation during the past 2000 years. Science 354, 760–764 (2016).
Bovine HapMap, C. et al. Genome-wide survey of SNP variation uncovers the genetic structure of cattle breeds. Science 324, 528–532 (2009).
Wagschal, A. et al. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat. Med. 21, 1290–1297 (2015).
Plassais, J. et al. Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology. Nat. Commun. 10, 1489 (2019).
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).
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.
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).
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).
Kornfeld, J. W. et al. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of HNF1B. Nature 494, 111–115 (2013).
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).
Butler, A. E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).
Kameswaran, V. et al. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab. 19, 135–145 (2014).
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).
Jin, T. The WNT signalling pathway and diabetes mellitus. Diabetologia 51, 1771–1780 (2008).
Belgardt, B. F. et al. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat. Med. 21, 619–627 (2015).
Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).
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).
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).
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).
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).
Najafi-Shoushtari, S. H. et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328, 1566–1569 (2010).
Rayner, K. J. et al. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573 (2010).
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).
Ramirez, C. M. et al. Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ. Res. 112, 1592–1601 (2013).
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).
Goedeke, L. et al. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat. Med. 21, 1280–1289 (2015).
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).
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).
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).
Rottiers, V. et al. MicroRNAs in metabolism and metabolic diseases. Cold Spring Harb. Symp. Quant. Biol. 76, 225–233 (2011).
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).
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).
Goedeke, L. et al. A regulatory role for microRNA 33* in controlling lipid metabolism gene expression. Mol. Cell Biol. 33, 2339–2352 (2013).
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).
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).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).
Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).
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).
Vickers, K. C. et al. MicroRNA-27b is a regulatory hub in lipid metabolism and is altered in dyslipidemia. Hepatology 57, 533–542 (2013).
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).
Vickers, K. C. et al. MicroRNA-223 coordinates cholesterol homeostasis. Proc. Natl Acad. Sci. USA 111, 14518–14523 (2014).
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).
Xu, Y. et al. A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism. Nat. Commun. 6, 7466 (2015).
Singaravelu, R. et al. MicroRNA-7 mediates cross-talk between metabolic signaling pathways in the liver. Sci. Rep. 8, 361 (2018).
Breslow, J. L. Mouse models of atherosclerosis. Science 272, 685–688 (1996).
Masucci-Magoulas, L. et al. A mouse model with features of familial combined hyperlipidemia. Science 275, 391–394 (1997).
Horie, T. et al. MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice. J. Am. Heart Assoc. 1, e003376 (2012).
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.
Ouimet, M. et al. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J. Clin. Invest. 125, 4334–4348 (2015).
Cheng, J. et al. MicroRNA-144 silencing protects against atherosclerosis in male, but not female mice. Arterioscler. Thromb. Vasc. Biol. 40, 412–425 (2020).
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).
Wan, Y. et al. Regulation of cellular senescence by miR-34a in alcoholic liver injury. Am. J. Pathol. 187, 2788–2798 (2017).
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).
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.
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).
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).
Lee, Y. S. et al. Silencing by small RNAs is linked to endosomal trafficking. Nat. Cell Biol. 11, 1150–1156 (2009).
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).
Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).
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).
Mori, M. A. et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J. Clin. Invest. 124, 3339–3351 (2014).
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.
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).
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.
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.
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).
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).
Sedgeman, L. R. et al. Beta cell secretion of miR-375 to HDL is inversely associated with insulin secretion. Sci. Rep. 9, 3803 (2019).
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).
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).
Sangalli, E. et al. Circulating microRNA-15a associates with retinal damage in patients with early stage type 2 diabetes. Front. Endocrinol. 11, 254 (2020).
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).
Buchanan, T. A. & Xiang, A. H. Gestational diabetes mellitus. J. Clin. Invest. 115, 485–491 (2005).
Yoffe, L. et al. Early diagnosis of gestational diabetes mellitus using circulating microRNAs. Eur. J. Endocrinol. 181, 565–577 (2019).
Ebert, M. S. & Sharp, P. A. Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).
Doyle, J. C., Francis, B. A. & Tannenbaum, A. R. Feedback Control Theory (Courier Corporation, 2013).
Cassidy, J. J. et al. Repressive gene regulation synchronizes development with cellular metabolism. Cell 178, 980–992 e917 (2019).
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).
The authors declare no competing interests.
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.
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.
About this article
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). https://doi.org/10.1038/s41580-021-00354-w