Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis

Diabetes Obes Metab. 2016 Feb;18(2):142-51. doi: 10.1111/dom.12590. Epub 2015 Dec 23.

Abstract

Aims: 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.

Keywords: antidiabetic drug; fatty liver; insulin resistance; renal steatosis; retinoids; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoates / therapeutic use
  • Biphenyl Compounds / therapeutic use
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / adverse effects
  • Drugs, Investigational / therapeutic use
  • Hyperglycemia / prevention & control*
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Lipid Peroxidation / drug effects
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / prevention & control*
  • Obesity / complications
  • Oxidative Stress / drug effects
  • Pancreas / drug effects
  • Pancreas / metabolism
  • Pancreas / pathology
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Retinoic Acid / metabolism
  • Thiazoles / therapeutic use

Substances

  • 4'-octyl-4-biphenylcarboxylic acid
  • 4-(4-(2-(n-butoxy)ethoxy)-5-methylthiazol-2-yl)-2-fluorobenzoic acid
  • Benzoates
  • Biphenyl Compounds
  • Drugs, Investigational
  • Hypoglycemic Agents
  • Receptors, Retinoic Acid
  • Thiazoles
  • retinoic acid receptor beta
  • retinoic acid receptor beta2, mouse