Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a Mouse Rdh10 Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism

被引：41

作者：

Yang, Di ^{[1
,2
]}

Vuckovic, Marta G. ^{[2
]}

Smullin, Carolyn P. ^{[2
]}

Kim, Myeongcheol ^{[2
]}

Lo, Christabel Pui-See ^{[2
]}

Devericks, Emily ^{[2
]}

Yoo, Hong Sik ^{[2
]}

Tintcheva, Milena ^{[2
]}

Deng, Yinghua ^{[2
]}

Napoli, Joseph L. ^{[1
,2
]}

机构：

[1] Univ Calif Berkeley, Grad Program Metab Biol, Berkeley, CA 94720 USA

[2] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

来源：

DIABETES | 2018年 / 67卷 / 04期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

VITAMIN-A; DEHYDROGENASE; 10; RECEPTOR; DIFFERENTIATION; BIOSYNTHESIS; ESTROGEN; SPERMATOGENESIS; IDENTIFICATION; HOMEOSTASIS; MECHANISMS;

D O I：

10.2337/db17-0946

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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) panagonist 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.

引用

页码：662 / 673

页数：12