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

Aims: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease. Methods: Synthetic agonists for RAR beta 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). Results: We show that administration of synthetic agonists for RAR beta 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 beta 2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RAR beta 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 beta-oxidation, such as CPT1 alpha, in these organs. RAR beta 2 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 RAR beta 2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RAR beta 2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.