Comparative analysis of thyroid hormone systems in rodents with subterranean lifestyle

Abstract

African mole-rats are subterranean rodents inhabiting underground burrows. This habitat entails risks of overheating, hypoxia, and scarce food availability. Consequently, many subterranean species have evolved low basal metabolism and low body temperature, but the regulation of these traits at the molecular level were unknown. Measurements of serum thyroid hormone (TH) concentrations in African mole-rats have revealed a unique TH phenotype, which deviates from the typical mammalian pattern. Since THs are major regulators of metabolic rate and body temperature, we further characterised the TH system of two African mole-rat species, the naked mole-rat (Heterocephalus glaber) and the Ansell’s mole-rat (Fukomys anselli) at the molecular level in a comparative approach involving the house mouse (Mus musculus) as a well-studied laboratory model in TH research. Most intriguingly, both mole-rat species had low iodide levels in the thyroid and naked mole-rats showed signs of thyroid gland hyperplasia. However, contrary to expectations, we found several species-specific differences in the TH systems of both mole-rat species, although ultimately resulting in similar serum TH concentrations. These findings indicate a possible convergent adaptation. Thus, our study adds to our knowledge for understanding adaptations to the subterranean habitat.

Low thyroxine serves as an upstream regulator of ecophysiological adaptations in Ansell’s mole-rats

“…Low RMR and low T b are considered important convergent ecophysiological adaptations to these ecological challenges in African mole-rats ( 3 , 6 ), but the upstream regulation of these important physiological traits was unknown thus far. We have previously described peculiarities of the TH system of naked and Ansell’s mole-rats involving serum TH concentrations, the HPT axis, and peripheral TH metabolism by deiodinases ( 27 , 28 , 42 ). Because THs are important regulators of metabolic rate and thermoregulation ( 11 ), we hypothesized that the bathyergid TH system serves as the upstream regulator of low RMR as well as low T b .…”

“…On the other hand, other expected hallmarks of HPT axis response to elevated TH levels such as downregulation of Trh expression in the hypothalamus were lacking. It has often been questioned whether the negative feedback loop of the HPT axis is functional in mole-rats, because of the extraordinarily low serum T4 concentrations in naked and Ansell’s mole-rats ( 26 – 28 ). Our data strongly indicate that TH synthesis is negatively regulated by a pituitary-thyroid axis, but it is still questionable to which extent the hypothalamus contributes to negative feedback regulation.…”

“…The second explanatory approach is supported by higher serum rT3 concentrations and a lower TT3/TT4 ratio, indicating higher T4 inactivation and lower conversion of T4 into the active T3, respectively. In a previous study, we measured hepatic DIO1 activity in untreated mole-rats, which was very low and even not detectable in 4 out of 7 animals ( 28 ). Although hepatic DIO1 activity did not differ between vehicle- and T4-treated animals in the present study, it was obviously increased compared to untreated animals, providing a possible mechanism for the limited upregulation of RMR.…”

“…This assay is specifically designed for measurement using the Qubit Fluorometer (Invitrogen, Carlsbad, CA, USA), which is the gold standard for quantification of cDNA for next generation sequencing ( 34 – 36 ). The applicability of this method as a suitable alternative to housekeeping gene-based normalization was previously validated ( 28 ).…”

“…DEHAL activity was measured in a comparable setup to DIO1 for detecting enzyme-mediated iodide release, using mono-iodo-tyrosine (10 µM) as substrate. By using 15 µg protein for thyroid, and 80 µg protein from liver and kidney homogenate, with an incubation time of 2 (thyroid) or 4 (liver and kidney) hours, the DEHAL activity was determined as described before ( 28 ).…”