Effect of ecdysterone on the hepatic transcriptome and lipid metabolism in lean and obese Zucker rats

Ecdysteroids are a class of steroid hormones occurring in insects, where they are referred as zooecdysteroids, and in plants, where they are termed phytoecdysteroids. While zooecdysteroids in insects regulate important developmental processes, such as embryogenesis, molting (ecdysis), metamorphosis, reproduction, and diapause, phytoecdysteroids provide protection against invertebrate predators by acting as feeding deterrents and by disrupting critical developmental processes of such invertebrates. The ecdysteroids in insects and plants comprise a great number of different analogues, with 20‐hydroxyecdysone, also called ecdysterone, being the quantitatively dominating biologically active analogue in both, insects and plants. Although phytoecdysteroids are effective toxins or antifeedants towards non-adapted herbivorous invertebrate predators, ecdysteroids are apparently non-toxic to mammals and even have been shown to exert a variety of interesting metabolic actions, such as antiobesity, hypoglycemic and protein-anabolic effects. In the present study aimed to test the hypothesis that ecdysterone causes lipid-lowering effects in obese Zucker rats. To test this hypothesis, two groups of obese Zucker rats were fed a nutrient-adequate diet supplemented without or with 0.05% ecdysterone. This ecdysterone concentration was appropriate to achieve a similar dose of ecdysterone per kg body weight BW as applied in other rodent studies, in which ecdysterone caused either hepatic and plasma lipid-lowering effects or antiobesity effects in different rodent models. In order to decipher the potential lipid-lowering actions of ecdysteroids in Zucker rats, measurements of liver and plasma lipid concentrations and hepatic transcriptome analysis was carried out. To further study if ecdysterone is capable of alleviating the strong lipid-synthetic activity in the liver of obese Zucker rats, the study included also two groups of lean Zucker rats which also received either the ecdysterone-supplemented or the non-supplemented diet.蜕皮类固醇（Ecdysteroids）是一类广泛存在于昆虫与植物中的类固醇激素：在昆虫体内被称为动物蜕皮类固醇（zooecdysteroids），在植物体内则被称为植物蜕皮类固醇（phytoecdysteroids）。昆虫体内的动物蜕皮类固醇可调控诸多关键发育过程，包括胚胎发生、蜕皮（蜕壳）、变态发育、繁殖以及滞育；而植物蜕皮类固醇可通过充当拒食剂、扰乱无脊椎捕食者的关键发育进程，为植物提供针对无脊椎天敌的保护屏障。昆虫与植物中的蜕皮类固醇包含大量结构各异的类似物，其中20-羟基蜕皮酮（20-hydroxyecdysone，又称蜕皮甾酮ecdysterone）是昆虫与植物体内含量最丰富、活性最强的生物活性类似物。尽管植物蜕皮类固醇对未产生适应性的植食性无脊椎捕食者而言是有效的毒素或拒食剂，但蜕皮类固醇对哺乳动物并无明显毒性，甚至被证实可发挥多种有益的代谢调控作用，如抗肥胖、降血糖以及促进蛋白质合成的代谢效应。本研究旨在验证蜕皮甾酮可在肥胖Zucker大鼠中产生降血脂效应这一科学假说。为验证该假说，研究将两组肥胖Zucker大鼠分别饲喂营养均衡的基础日粮：一组日粮未添加蜕皮甾酮，另一组则添加0.05%的蜕皮甾酮。该添加浓度可使每千克体重（BW）的蜕皮甾酮给药剂量与其他啮齿类动物研究中的给药剂量相当——在这些既往研究中，蜕皮甾酮在不同啮齿类动物模型中均表现出肝脏与血浆脂质降低效应，或抗肥胖活性。为解析蜕皮类固醇在Zucker大鼠体内潜在的降血脂作用机制，本研究对大鼠肝脏与血浆的脂质浓度进行了定量检测，并开展了肝脏转录组分析。为进一步探究蜕皮甾酮是否能够缓解肥胖Zucker大鼠肝脏内旺盛的脂质合成活性，本研究还增设了两组瘦型Zucker大鼠，分别饲喂添加蜕皮甾酮与未添加蜕皮甾酮的对照日粮。