Molecular mechanisms regulating seasonal physiology
Final Report Abstract
Seasonal mammals undergo pronounced physiological changes in order to survive the energetic bottlenecks caused by winter. Driven by changes in day length, Djungarian hamsters change their fur, cease reproduction and adjust body weight and metabolism in order to maintain energy balance throughout the year. Thyroid hormone (T3) metabolism specifically in the hypothalamus has been identified as crucial factor for seasonal physiological changes in body weight and reproduction. Here we demonstrate, that thyroid hormones are also involved in torpor regulation. Torpor is a state of metabolic depression Djungarian hamsters spontaneously undergo once winter adapted. During their circadian resting time, they decrease metabolic rate by 75 % and consequently body temperature drops to values between 15 and 25 °C. In our studies we could show that hyperthyroidism induced by giving T3 via drinking water potently inhibited torpor, whereas hypothyroidism induced by methimazole+perchlorate via drinking water promoted torpor behaviour. Gene expression analysis revealed that thyroid hormone status mainly affected the expression of uncoupling proteins in brown adipose tissue that are involved in the regulation of adaptive thermogenesis. Manipulation T3 concentrations exclusively in the hypothalamus support the hypothesis that T3 availability within the hypothalamus significantly contributes to the regulation of daily torpor via a central pathway. To uncover central pathways of torpor induction, we screened the hypothalamus for differential gene expression during torpor entrance by Illumina sequencing. Transcriptome analysis revealed 284 differentially regulated genes, 181 upregulated and 103 downregulated. Amongst the top 20 upregulated genes, we found a significant number of genes coding for proteins involved in structural changes and transport of biomolecules (5 collagens, myosin, dynein). qPCR validation suggested that these gene´s expression is specifically initiated in the early state of torpor and likely reflect protective molecular adaptions during metabolic depression. In a second set of experiments, we compared gene expression of hypothalamic systems that have previously been described to be involved in metabolic regulation between different torpor forms (spontaneous and fasting induced torpor) of Djungarian hamsters. Spontaneous and fasting induced torpor differ in timing, depth, duration and fuel utilization and have been suggested to rely on different mechanisms. Whereas the results revealed phase shifted expression of clock genes in the circadian clock, only subtle differences were found in the orexigenic system of the arcuate nucleus. Analysis of thyroid hormone related genes suggest reduced hypothalamic T3 availability in both torpor forms. Taken together, our results provide evidence that spontaneous and fasting induced torpor differ in certain but not all central control mechanisms. This however, should be carefully taken into account when interpreting data in torpor research, especially from animal models of fasting-induced hypometabolism such as mice. The data derived from this project have provided new insights on regulatory pathways of metabolic depression that in the long term, we aim to identify.
Publications
- Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element of circannual timing in the Siberian hamster (Phodopus sungorus). PLoS One 2013
Herwig A, de Vries EM, Bolborea M, Wilson D, Mercer JG, Ebling FJ, Morgan PJ, Barrett P
(See online at https://doi.org/10.1371/journal.pone.0062003) - Reduction of body temperature governs neutrophil retention in hibernating and nonhibernating animals by margination. J Leukoc Biol 2013; 94:431-437
Bouma HR, Dugbartey GJ, Boerema AS, Talaei F, Herwig A, Goris M, van Buiten A, Strijkstra AM, Carey HV, Henning RH, Kroese FG
(See online at https://dx.doi.org/10.1189/jlb.0611298) - A thyroid hormone challenge in hypothyroid rats identifies T3 regulated genes in the hypothalamus and in models with altered energy balance and glucose homeostasis. Thyroid 2014; 24: 1575-1593
Herwig A, Campbell G, Mayer CD, Boelen A, Anderson R, Ross AW, Mercer JG, Barrett P
(See online at https://doi.org/10.1089/thy.2014.0169) - Platelet dynamics during natural and pharmacologically induced torpor. PLoS One 2014
De Vrij EL, Vogelaar PC, Goris M, Houwertjes MC, Herwig A, Dugbartey GJ, Boerema AS, Strijkstra AM, Bouma HR, Henning RH
(See online at https://doi.org/10.1371/journal.pone.0093218) - Thyroid hormone status affects expression of daily torpor and gene transcription in Djungarian hamsters (Phodopus sungorus). Hormones and Behavior 2015; 75:120-129
Bank JHH, Kemmling J, Rijntjes E, Wirth EK, Herwig A
(See online at https://doi.org/10.1016/j.yhbeh.2015.09.006) - Orchestration of gene expression across the seasons: Hypothalamic gene expression in natural photoperiod throughout the year in the Siberian hamster. Scientific Reports 2016; 6:29689
Petri I, Diedrich V, Wilson D, Fernández-Calleja J, Herwig A, Steinlechner S, Barrett P
(See online at https://doi.org/10.1038/srep29689) - The Chemistry of Cold: Mechanisms of Torpor Regulation in the Siberian Hamster. Physiology (Bethesda) 2016, 31:51-59
Cubuk C, Bank JH, Herwig A
(See online at https://dx.doi.org/10.1152/physiol.00028.2015) - Gene expression analysis and microdialysis suggest hypothalamic triiodothyronine (T3) gates daily torpor in Djungarian hamsters (Phodopus sungorus). J Comp Physiol B 2017; 187:857-868
Bank JHH, Cubuk C, Wilson D, Rijntjes E, Kemmling J, Markowsky H, Barrett P, Herwig A
(See online at https://doi.org/10.1007/s00360-017-1086-5) - Transcriptome analysis of hypothalamic gene expression during daily torpor in Djungarian hamsters (Phodopus sungorus). Frontiers Neuroendocrinol, Front Neurosci 2017
Cubuk C, Kemmling J, Fabrizius A, Herwig A
(See online at https://doi.org/10.3389/fnins.2017.00122)
