title: Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis.
abstract: OBJECTIVE
  To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease.
  
  
  METHODS
  Synthetic agonists for RARβ2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D).
  
  
  RESULTS
  We show that administration of synthetic agonists for RARβ2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARβ2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARβ2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid β-oxidation, such as CPT1α, in these organs. RARβ2 agonists lower triglyceride levels in these organs, and in muscle.
  
  
  CONCLUSIONS
  Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARβ2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARβ2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Trasino
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
authors.forename: X-H
authors.initials: XH
authors.lastname: Tang
authors.affiliation: Department of Pathology, Weill Cornell Medical College of Cornell University/New York Presbyterian Hospital, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jessurun
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, NY, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D000818:Animals; D001565:Benzoates / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D015507:Drugs, Investigational / Q000627:therapeutic use; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000517:prevention & control*; D009765:Obesity / Q000150:complications; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use
chemical_list: C507710:4'-octyl-4-biphenylcarboxylic acid; C507711:4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; D015507:Drugs, Investigational; D007004:Hypoglycemic Agents; D018168:Receptors, Retinoic Acid; D013844:Thiazoles; C082925:retinoic acid receptor beta; C000611841:retinoic acid receptor beta2, mouse
keywords: antidiabetic drug; fatty liver; insulin resistance; renal steatosis; retinoids; type 2 diabetes