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Diabetes ; 67(4): 662-673, 2018 04.
Article in English | MEDLINE | ID: mdl-29321172

ABSTRACT

Pharmacological dosing of all-trans-retinoic acid (atRA) controls adiposity in rodents by inhibiting adipogenesis and inducing fatty acid oxidation. Retinol dehydrogenases (Rdh) catalyze the first reaction that activates retinol into atRA. This study examined postnatal contributions of Rdh10 to atRA biosynthesis and physiological functions of endogenous atRA. Embryonic fibroblasts from Rdh10 heterozygote hypomorphs or with a total Rdh10 knockout exhibit decreased atRA biosynthesis and escalated adipogenesis. atRA or a retinoic acid receptor (RAR) pan-agonist reversed the phenotype. Eliminating one Rdh10 copy in vivo (Rdh10+/- ) yielded a modest decrease (≤25%) in the atRA concentration of liver and adipose but increased adiposity in male and female mice fed a high-fat diet (HFD); increased liver steatosis, glucose intolerance, and insulin resistance in males fed an HFD; and activated bone marrow adipocyte formation in females, regardless of dietary fat. Chronic dosing with low-dose atRA corrected the metabolic defects. These data resolve physiological actions of endogenous atRA, reveal sex-specific effects of atRA in vivo, and establish the importance of Rdh10 to metabolic control by atRA. The consequences of a modest decrease in tissue atRA suggest that impaired retinol activation may contribute to diabesity, and low-dose atRA therapy may ameliorate adiposity and its sequelae of glucose intolerance and insulin resistance.


Subject(s)
Adipogenesis/genetics , Adipose Tissue/metabolism , Alcohol Oxidoreductases/genetics , Lipid Metabolism/genetics , Liver/metabolism , Tretinoin/metabolism , Adipogenesis/drug effects , Adiposity/genetics , Animals , Diet, High-Fat , Female , Fibroblasts/metabolism , Glucose Intolerance/metabolism , Heterozygote , Insulin Resistance/genetics , Lipid Metabolism/drug effects , Male , Mice , Non-alcoholic Fatty Liver Disease/metabolism , Oxidation-Reduction , Receptors, Retinoic Acid/agonists , Sex Factors , Tretinoin/pharmacology , Vitamin A/metabolism
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