MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids.

Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

[1]  R. Jove,et al.  miR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis , 2014, Oncogene.

[2]  S. Kauppinen,et al.  Pharmacological Inhibition of a MicroRNA Family in Nonhuman Primates by a Seed-Targeting 8-Mer AntimiR , 2013, Science Translational Medicine.

[3]  A. Riggs,et al.  MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation , 2013, Proceedings of the National Academy of Sciences.

[4]  S. Kauppinen,et al.  Treatment of HCV infection by targeting microRNA. , 2013, The New England journal of medicine.

[5]  J. Olefsky,et al.  The Origins and Drivers of Insulin Resistance , 2013, Cell.

[6]  M. Stoffel,et al.  Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b , 2013, Nature.

[7]  E. Olson,et al.  MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. , 2013, The Journal of clinical investigation.

[8]  P. Chambon,et al.  Diabetes Risk Gene and Wnt Effector Tcf7l2/TCF4 Controls Hepatic Response to Perinatal and Adult Metabolic Demand , 2012, Cell.

[9]  E. Olson,et al.  MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles , 2012, Nature Reviews Drug Discovery.

[10]  S. Kauppinen,et al.  Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function , 2012, Proceedings of the National Academy of Sciences.

[11]  D. Moore,et al.  Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver , 2012, Hepatology.

[12]  E. Liao.  Management of type 2 diabetes: new and future developments in treatment. , 2012, The American journal of medicine.

[13]  M. White,et al.  Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 , 2012, Diabetologia.

[14]  D. Moore.  Nuclear receptors reverse McGarry's vicious cycle to insulin resistance. , 2012, Cell metabolism.

[15]  C. Newgard.  Interplay between lipids and branched-chain amino acids in development of insulin resistance. , 2012, Cell metabolism.

[16]  A. Näär,et al.  MicroRNAs in metabolism and metabolic disorders , 2012, Nature Reviews Molecular Cell Biology.

[17]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[18]  G. Shulman,et al.  Mechanisms for Insulin Resistance: Common Threads and Missing Links , 2012, Cell.

[19]  S. Lowe,et al.  The microcosmos of cancer , 2012, Nature.

[20]  W. Ruf,et al.  Tissue factor-PAR2 signaling promotes diet-induced obesity and adipose inflammation , 2011, Nature Medicine.

[21]  D. Accili,et al.  Hormonal regulation of hepatic glucose production in health and disease. , 2011, Cell metabolism.

[22]  M. Zavolan,et al.  MicroRNAs 103 and 107 regulate insulin sensitivity , 2011, Nature.

[23]  C. Kahn,et al.  PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans. , 2011, The Journal of clinical investigation.

[24]  J. Brüning,et al.  Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism , 2011, Nature Cell Biology.

[25]  M. White,et al.  Regulation of glucose homeostasis through a XBP-1–FoxO1 interaction , 2011, Nature Medicine.

[26]  R. Jove,et al.  miR‐194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice , 2010, Hepatology.

[27]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[28]  R. Coleman,et al.  Acyl-coenzyme A synthetases in metabolic control , 2010, Current opinion in lipidology.

[29]  M. Siomi,et al.  Posttranscriptional regulation of microRNA biogenesis in animals. , 2010, Molecular cell.

[30]  S. Wakil,et al.  Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease , 2009, Proceedings of the National Academy of Sciences.

[31]  D. Mashek,et al.  Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity* , 2009, The Journal of Biological Chemistry.

[32]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[33]  M. Patti,et al.  The emerging genetic architecture of type 2 diabetes. , 2008, Cell metabolism.

[34]  B. Doble,et al.  Tissue-Specific Role of Glycogen Synthase Kinase 3β in Glucose Homeostasis and Insulin Action , 2008, Molecular and Cellular Biology.

[35]  R. Bartrons,et al.  Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice , 2008, Diabetes.

[36]  A. Hamsten,et al.  Genes Involved in Fatty Acid Partitioning and Binding, Lipolysis, Monocyte/Macrophage Recruitment, and Inflammation Are Overexpressed in the Human Fatty Liver of Insulin-Resistant Subjects , 2007, Diabetes.

[37]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[38]  R. Hammer,et al.  Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene , 2004, Trends in Endocrinology & Metabolism.

[39]  M. Magnuson,et al.  Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre Recombinase* , 1999, The Journal of Biological Chemistry.

[40]  U. Fischer,et al.  Intronic miR-26b controls neuronal differentiation by repressing its host transcript, ctdsp2. , 2012, Genes & development.

[41]  Jinu Kim,et al.  MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer , 2010 .

[42]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.