Retinoic acid receptor ?2 agonists restore glycaemic control in diabetes and reduce steatosis.

ABSTRACT: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease.Synthetic agonists for RAR?2 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).We show that administration of synthetic agonists for RAR?2 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, RAR?2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RAR?2 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 ?-oxidation, such as CPT1?, in these organs. RAR?2 agonists lower triglyceride levels in these organs, and in muscle.Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RAR?2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RAR?2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.

SUBMITTER: Trasino SE 

PROVIDER: S-EPMC4948868 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature