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

TitleRetinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsTrasino SE, Tang X-H, Jessurun J, Gudas LJ
JournalDiabetes Obes Metab
Volume18
Issue2
Pagination142-51
Date Published2016 Feb
ISSN1463-1326
KeywordsAnimals, Benzoates, Biphenyl Compounds, Diabetes Mellitus, Type 2, Diet, High-Fat, Drugs, Investigational, Hyperglycemia, Hypoglycemic Agents, Insulin Resistance, Kidney, Lipid Peroxidation, Liver, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Muscle, Skeletal, Non-alcoholic Fatty Liver Disease, Obesity, Oxidative Stress, Pancreas, Receptors, Retinoic Acid, Thiazoles
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.

DOI10.1111/dom.12590
Alternate JournalDiabetes Obes Metab
PubMed ID26462866
PubMed Central IDPMC4948868
Grant ListR01 CA043796 / CA / NCI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
TG CA062948 / CA / NCI NIH HHS / United States
Related Faculty: 
Jose Jessurun, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700