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Retinoic acid receptor β2 agonists restore glycaemic control in diabetes and reduce steatosis
Author(s) -
Trasino S. E.,
Tang X.H.,
Jessurun J.,
Gudas L. J.
Publication year - 2016
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12590
Subject(s) - endocrinology , medicine , lipogenesis , steatosis , type 2 diabetes , retinoic acid receptor , fatty acid synthase , triglyceride , insulin resistance , insulin , fatty liver , chemistry , retinoic acid , diabetes mellitus , biology , cholesterol , lipid metabolism , biochemistry , disease , gene
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.