DataSheet_1_Vitamin A regulates tissue-specific organ remodeling in diet-induced obesity independent of mitochondrial function.pdf

BackgroundPerturbed mitochondrial energetics and vitamin A (VitA) metabolism are associated with the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes (T2D).
MethodsTo test the hypothesis that VitA regulates tissue-specific mitochondrial energetics and adverse organ remodeling in DIO, we utilized a murine model of impaired VitA availability and high fat diet (HFD) feeding. Mitochondrial respiratory capacity and organ remodeling were assessed in liver, skeletal muscle, and kidney tissue, which are organs affected by T2D-associated complications and are critical for the pathogenesis of T2D.
ResultsIn liver, VitA had no impact on maximal ADP-stimulated mitochondrial respiratory capacity (VADP) following HFD feeding with palmitoyl-carnitine and pyruvate each combined with malate as substrates. Interestingly, histopathological and gene expression analyses revealed that VitA mediates steatosis and adverse remodeling in DIO. In skeletal muscle, VitA did not affect VADP following HFD feeding. No morphological differences were detected between groups. In kidney, VADP was not different between groups with both combinations of substrates and VitA transduced the pro-fibrotic transcriptional response following HFD feeding.
ConclusionThe present study identifies an unexpected and tissue-specific role for VitA in DIO that regulates the pro-fibrotic transcriptional response and that results in organ damage independent of changes in mitochondrial energetics.

背景：线粒体能量代谢紊乱与维生素A（Vitamin A, VitA）代谢异常，与饮食诱导肥胖（Diet-induced obesity, DIO）及2型糖尿病（Type 2 diabetes, T2D）的发病机制密切相关。
方法：为验证“维生素A可调控饮食诱导肥胖中组织特异性线粒体能量代谢与器官异常重构”这一假说，本研究采用维生素A可利用性受损的小鼠模型，并给予高脂饮食（High fat diet, HFD）干预。选取与2型糖尿病并发症相关且在其发病机制中发挥关键作用的肝脏、骨骼肌及肾脏组织，对线粒体呼吸容量与器官重构情况进行检测评估。
结果：在肝脏组织中，当以棕榈酰肉碱、丙酮酸分别与苹果酸联合作为底物进行高脂饮食喂养后，维生素A对ADP刺激的最大线粒体呼吸容量（VADP）无显著影响。值得注意的是，组织病理学与基因表达分析显示，维生素A可介导饮食诱导肥胖中的脂肪变性及器官异常重构。在骨骼肌组织中，高脂饮食喂养后维生素A对VADP水平无影响，两组间未检测到形态学差异。在肾脏组织中，两种底物组合下的VADP水平在两组间均无显著差异，且高脂饮食喂养后维生素A可诱导促纤维化转录反应。
结论：本研究揭示了维生素A在饮食诱导肥胖中一种未被预期的组织特异性调控作用——其可调控促纤维化转录反应，并在不依赖线粒体能量代谢变化的情况下造成器官损伤。