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

• Applicant: Dr. Yoshiyuki Henning
• Subject Area: Animal Physiology and Biochemistry
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409806707

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.

• DFG Programme: Research Grants