title: MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue.
abstract: BACKGROUND
  The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function.
  
  
  OBJECTIVE
  To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity.
  
  
  RESULTS
  MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression.
  
  
  CONCLUSIONS
  Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or Pleckstrin homology domain leucine-rich repeat protein phosphatase inhibitors may represent a new therapeutic approach to ameliorate insulin resistance by improving adipose tissue endothelial Akt-endothelial nitric oxide synthase-nitric oxide signaling.
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Jibin
authors.initials: J
authors.lastname: Lin
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Sona
authors.initials: S
authors.lastname: Kang
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Nathan
authors.initials: N
authors.lastname: Belkin
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Akm K
authors.initials: AK
authors.lastname: Wara
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.).
authors.forename: Dazhu
authors.initials: D
authors.lastname: Li
authors.affiliation: From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (X.S., J.L., N.B., A.K.W., B.I., M.W.F.); Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (J.L., D.L.); Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong SAR, China (Y.Z.); Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Center for Life Sciences, Beth Israel Deaconess Medical Center, Boston, MA (S.K.); and Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (N.M.H.). mfeinberg@partners.org.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D035683:MicroRNAs / Q000096:biosynthesis*
chemical_list: D001786:Blood Glucose; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse
keywords: PHLPP2; adipose tissue; endothelial cells; insulin resistance; microRNA; obesity
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