Altered thyroid hormone physiology in rodents – a convergent adaptation to harsh environmental conditions

啮齿动物甲状腺激素生理学的改变——对恶劣环境条件的趋同适应

• 批准号: 409806707
• 负责人: Dr. Yoshiyuki Henning
• 金额: --
• 依托单位: Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/409806707?language=en
• 关键词: Altered; thyroid; hormone; physiology; rodents

Thyroid hormones (THs), i.e. triiodothyronine (T3) and its prohormone thyroxine (T4), are versatile hormones pivotal for e.g. energy homeostasis in all animals. The serum ratio between T3 and T4 was long considered basically conserved across all animal taxa. However, own studies have shown that Fukomys mole-rats, African rodents with a subterranean lifestyle, have constantly downregulated serum T4 levels, while T3 is circulating in the rodent-typical range. The combination of reptilian-like T4 levels and normal T3 levels is considered pathological in animals including humans, but mole-rats do not exhibit any impairments associated with this unique TH ratio. Instead, we have strong indications that TH signaling is actively downregulated in metabolically active tissues (facultative TH resistance), which is in line with the necessity of keeping metabolic rate low in underground burrows, to avoid overheating and to cope with low food availability. Interestingly, similarly low T4 levels were reported for other rodent species, which are phylogenetically unrelated, but inhabit self-dug burrow systems (here: fossorial), indicating that this TH ratio might represent a yet unknown convergent ecophysiological adaptation. Thus, the proposed project aims to investigate proximate and ultimate mechanisms of such a unique TH system in an interdisciplinary and comparative approach in six phylogenetically unrelated rodent species involving endocrinological, genetical, and physiological methods. We hypothesize that downregulation of serum T4 is important to maintain a low resting metabolic rate. This hypothesis is supported by an own study, where we have shown that T4 supplementation in a Fukomys mole-rat species does not lead to elevated resting metabolic rates. To validate this concept systematically, comparative, descriptive, and functional approaches will be combined. In concrete terms, we plan to (1) characterize gene expression levels of regulatory components involved in TH signaling and metabolic rate regulation in four fossorial and two surface-dwelling rodent species, and (2) analyze the effects of T4 supplementation on metabolic rate regulation as well as thermoregulation with molecularbiological and physiological methods, to identify tissue-specific as well as systemic effects in two fossorial and one surface-dwelling species. The results gained in the proposed project will enable us to infer ecophysiological and evolutionary mechanisms by which animals adapt to subterranean environmental conditions and will broaden our mind regarding the dynamic and versatile mechanisms of THs in regulating animal physiology in terms of different life histories. Comparative research with animals exhibiting an inherently unique TH status (which cannot be easily mimicked in other laboratory animals) also has the potential to reveal novel molecular mechanisms, which will help to understand unknown aspects in human metabolic disorders such as obesity and diabetes.

甲状腺激素（TH），即三碘甲状腺原氨酸（T3）及其激素原甲状腺素（T4），是对于例如所有动物中的能量稳态至关重要的多功能激素。T3和T4之间的血清比率长期以来被认为在所有动物分类群中基本上是保守的。然而，我们自己的研究表明，非洲啮齿类动物-一种生活在地下的啮齿类动物-不断下调血清T4水平，而T3则在啮齿类动物的典型范围内循环。爬行动物样T4水平和正常T3水平的组合在包括人类在内的动物中被认为是病理性的，但鼹鼠没有表现出与这种独特的TH比率相关的任何损伤。相反，我们有强烈的迹象表明，TH信号在代谢活性组织中被主动下调（兼性TH抗性），这符合地下洞穴中保持低代谢率的必要性，以避免过热并科普低食物可用性。有趣的是，其他啮齿类动物的T4水平也同样很低，这些啮齿类动物在遗传学上是不相关的，但它们栖息在自己挖的洞穴系统中（这里是fossorial），这表明这种TH比率可能代表了一种未知的趋同生理生态适应。因此，该项目的目的是调查近端和最终的机制，这样一个独特的TH系统在一个跨学科和比较的方法，在六个遗传学无关的啮齿动物物种，涉及内分泌学，遗传学和生理学的方法。我们推测血清T4的下调对于维持低的静息代谢率是重要的。这一假设得到了自己的一项研究的支持，在这项研究中，我们已经表明，T4补充剂在一个田鼠物种不会导致静息代谢率升高。为了系统地验证这一概念，比较，描述和功能的方法将结合起来。具体而言，我们计划（1）表征四种穴居啮齿动物和两种地表啮齿动物TH信号传导和代谢率调节相关调控组分的基因表达水平，（2）用分子生物学和生理学方法分析T4补充对代谢率调节和体温调节的影响。确定对两个穴居物种和一个地表栖息物种的组织特异性影响和系统性影响。在拟议的项目中获得的结果将使我们能够推断出生态生理学和进化机制，动物适应地下环境条件，并将扩大我们的头脑有关的动态和多功能的机制TH调节动物生理学在不同的生活史。与表现出固有独特TH状态的动物进行比较研究（在其他实验室动物中无法轻易模仿）也有可能揭示新的分子机制，这将有助于了解人类代谢紊乱（如肥胖和糖尿病）的未知方面。