Metabolic Benefits of MicroRNA-22 Inhibition.

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  • Author(s): Thibonnier M;Thibonnier M; Esau C; Esau C
  • Source:
    Nucleic acid therapeutics [Nucleic Acid Ther] 2020 Apr; Vol. 30 (2), pp. 104-116. Date of Electronic Publication: 2019 Dec 23.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE
    • Publication Information:
      Original Publication: New Rochelle, N.Y. : Mary Ann Liebert, Inc.
    • Subject Terms:
      Adipocytes/*drug effects ; Diabetes Mellitus/*therapy ; Energy Metabolism/*drug effects ; MicroRNAs/*genetics; Adipocytes/metabolism ; Animals ; Antagomirs/pharmacology ; Diabetes Mellitus/genetics ; Diabetes Mellitus/pathology ; Humans ; Insulin Resistance/genetics ; Jumonji Domain-Containing Histone Demethylases/genetics ; Lipid Peroxidation/drug effects ; Mice ; MicroRNAs/antagonists & inhibitors ; PPAR alpha/genetics ; RNA-Binding Proteins/genetics ; Sirtuin 1/genetics
    • Abstract:
      Diabesity is a growing pandemic with substantial health and financial consequences. We are developing microRNA (miRNA)-based drug candidates that transform fat storing adipocytes into fat burning adipocytes (browning effect) to treat metabolic diseases characterized by lipotoxicity. Through phenotypic screening in primary cultures of human subcutaneous adipocytes, we discovered that inhibition of miRNA-22-3p by several complementary antagomirs resulted in increased lipid oxidation, mitochondrial activity, and energy expenditure (EE). These effects may be mediated through activation of target genes like KDM3A , KDM6B , PPARA , PPARGC1B , and SIRT1 involved in lipid catabolism, thermogenesis, and glucose homeostasis. In the model of Diet-Induced Obesity in mice of various ages, weekly subcutaneous injections of various miRNA-22-3p antagomirs produced a significant fat mass reduction, but no change of appetite or body temperature. Insulin sensitivity, as well as circulating glucose and cholesterol levels, was also improved. These original findings suggest that miRNA-22-3p inhibition could become a potent treatment of human obesity and type 2 diabetes mellitus, the so-called diabesity characterized by lipotoxicity and insulin resistance.
    • Contributed Indexing:
      Keywords: adipocytes; diabetes; lipid oxidation; miRNAs; obesity; thermogenesis
    • Accession Number:
      0 (Antagomirs)
      0 (MIRN22 microRNA, human)
      0 (MicroRNAs)
      0 (PPAR alpha)
      0 (PPARA protein, human)
      0 (PPARGC1B protein, human)
      0 (RNA-Binding Proteins)
      EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
      EC 1.14.11.- (KDM3A protein, human)
      EC 1.14.11.- (KDM6B protein, human)
      EC 3.5.1.- (SIRT1 protein, human)
      EC 3.5.1.- (Sirtuin 1)
    • Publication Date:
      Date Created: 20191225 Date Completed: 20210705 Latest Revision: 20210705
    • Publication Date:
      20240105
    • Accession Number:
      10.1089/nat.2019.0820
    • Accession Number:
      31873061