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

甲状腺激素（THs），即三碘甲状腺原氨酸（T3）及其原激素甲状腺素（T4），是所有动物能量稳态的关键激素。长期以来，人们认为血清T3和T4比值在所有动物类群中基本保守。然而，自己的研究表明，Fukomys鼹鼠，一种生活在地下的非洲啮齿动物，血清T4水平持续下调，而T3在啮齿动物的典型范围内循环。在包括人类在内的动物中，类似爬行动物的T4水平和正常T3水平的结合被认为是病态的，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，在代谢活跃的组织中，TH信号被主动下调（兼性TH抗性），这与地下洞穴保持低代谢率的必要性是一致的，以避免过热和应对低食物供应。有趣的是，其他啮齿类动物也报告了类似的低T4水平，这些啮齿类动物与系统发育无关，但居住在自挖的洞穴系统中（此处为穴居动物），这表明这种TH比率可能代表了一种未知的趋同生态生理适应。因此，该项目旨在通过跨学科和比较的方法，在六种系统发育无关的啮齿动物物种中研究这种独特的TH系统的近似和最终机制，包括内分泌学，遗传学和生理学方法。我们假设血清T4的下调对维持低静息代谢率很重要。这一假设得到了我们自己的一项研究的支持，在该研究中，我们已经表明，在Fukomys鼹鼠物种中补充T4不会导致静息代谢率升高。为了系统地验证这一概念，将结合比较、描述和功能方法。具体而言，我们计划(1)表征四种穴居和两种地表居住啮齿动物中TH信号和代谢率调节相关调控成分的基因表达水平；(2)利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，以确定两种穴居和一种地表居住啮齿动物的组织特异性和系统性效应。该项目所获得的结果将使我们能够推断动物适应地下环境条件的生态生理和进化机制，并将开阔我们的视野，了解从不同生活史的角度来看，地下生物在调节动物生理方面的动态和多功能机制。与表现出固有独特TH状态的动物（在其他实验动物中不容易模仿）进行比较研究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。

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.