Thyroid hormone levels and expression of genes involved in the regulation of the thyroid system activity in male rats exposed to prolonged low temperatures and the effect of a thyroid-stimulating hormone receptor antagonist on these parameters

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Adaptation mechanisms to prolonged exposure to low temperatures, leading to increased thermogenesis and changes in metabolism, include increased activity of the hypothalamic-pituitary-thyroid (HPT) axis. In this regard, the current tasks are to study the balance of thyroid hormones (THs), the expression and activity of enzymes responsible for their synthesis in the thyroid gland (TG), the expression of the main components of the HPT axis, as well as to investigate the effect of thyroid stimulating hormone (TSH) receptor antagonists on these indicators when administered to animals exposed to cold. The aim of the work was to study the blood levels of TSH and THs and the expression of hypothalamic, pituitary and thyroid genes involved in the synthesis and secretion of TSH and THs in male rats that were kept for 10 days at low temperatures (+5°C), and to evaluate the effect of a single treatment of animals with the thieno[2,3-d]-pyrimidine derivative of TPY1, an allosteric antagonist of the TSH receptor developed by us, on these parameters. Rats exposed to cold developed T3-hyperthyroidism, which was associated with a decrease in the thyroxine level due to an increase in its conversion to T3, as indicated by an increase in the T3/T4 ratio and deiodinase type 2 (DIO2) expression in the TG. Compared with the control, the TG of hyperthyroid rats had an increased expression of the Tg and Nis genes encoding thyroglobulin and Na+/I-_symporter. TPY1 normalized the T3 level and decreased the expression of Tg and Nis, indicating a decrease in the TSH-stimulated activity of the TSH receptor by this TSH antagonist. TPY1 also increased the expression of the TSH β-subunit and thyroliberin receptor genes in the pituitary gland, which may be due to a higher threshold of sensitivity of thyrotrophs to the inhibitory effect of T3 under conditions of long-term T3 hyperthyroidism. A feature of cold-induced T3 hyperthyroidism in rats was the tissue specificity of changes in DIO2 gene expression, its increase in the TG and decrease in the hypothalamus, as well as the preservation of increased DIO2 gene expression in the TG after TPY1 treatment. Thus, prolonged exposure to cold leads to the development of pronounced T3 hyperthyroidism in rats with increased expression of genes responsible for the TH synthesis, and treatment with an allosteric antagonist of the TSH receptor significantly normalizes these indicators.

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Sobre autores

K. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Autor responsável pela correspondência
Email: derkatch_k@list.ru
Rússia, Saint-Petersburg

A. Pechalnova

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: derkatch_k@list.ru
Rússia, Saint-Petersburg

E. Chernenko

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: derkatch_k@list.ru
Rússia, Saint-Petersburg

I. Zorina

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: derkatch_k@list.ru
Rússia, Saint-Petersburg

A. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences

Email: derkatch_k@list.ru
Rússia, Saint-Petersburg

Bibliografia

  1. Laurberg P, Andersen S, Karmisholt J (2005) Cold adaptation and thyroid hormone metabolism. Horm Metab Res 37(9): 545–549. https://doi.org/10.1055/s-2005-870420
  2. Silva JE (2006) Thermogenic mechanisms and their hormonal regulation. Physiol Rev 86(2): 435–464. https://doi.org/10.1152/physrev.00009.2005
  3. Tsibulnikov S, Maslov L, Voronkov N, Oeltgen P (2020) Thyroid hormones and the mechanisms of adaptation to cold. Hormones (Athens) 19(3): 329–339. https://doi.org/10.1007/s42000-020-00200-2
  4. Filfilan WM (2023) Thyroid Hormones Regulate the Thermoregulatory Mechanisms of the Body: Review. Pak J Biol Sci 26(9): 453–457. https://doi.org/10.3923/pjbs.2023.453.457
  5. Silva JE, Bianco SD (2008) Thyroid-adrenergic interactions: physiological and clinical implications. Thyroid 18(2): 157–165. https://doi.org/10.1089/thy.2007.0252
  6. Bianco AC, Silva JE (1988) Cold exposure rapidly induces virtual saturation of brown adipose tissue nuclear T3 receptors. Am J Physiol 255(4 Pt 1): E496–E503. https://doi.org/10.1152/ajpendo.1988.255.4.E496
  7. Dutra SC, de Moura EG, Lisboa PC, Trevenzoli IH, Passos MC (2011) Leptin-programmed rats respond to cold exposure changing hypothalamic leptin receptor and thyroid function differently from cold-exposed controls. Regul Pept 171(1–3): 58–64. https://doi.org/10.1016/j.regpep.2011.07.005
  8. Iwen KA, Oelkrug R, Brabant G (2018) Effects of thyroid hormones on thermogenesis and energy partitioning. J Mol Endocrinol 60(3): R157–R170. https://doi.org/10.1530/JME-17-0319
  9. Yau WW, Yen PM (2020) Thermogenesis in Adipose Tissue Activated by Thyroid Hormone. Int J Mol Sci 21(8): 3020. https://doi.org/10.3390/ijms21083020
  10. Lee JY, Takahashi N, Yasubuchi M, Kim YI, Hashizaki H, Kim MJ, Sakamoto T, Goto T, Kawada T (2012) Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Physiol Cell Physiol 302(2): C463–C472. https://doi.org/10.1152/ajpcell.00010.2011
  11. Gavrila A, Hasselgren PO, Glasgow A, Doyle AN, Lee AJ, Fox P, Gautam S, Hennessey JV, Kolodny GM, Cypess AM (2017) Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status. Thyroid 27(1): 1–10. https://doi.org/10.1089/thy.2015.0646
  12. Castillo-Campos A, Gutiérrez-Mata A, Charli JL, Joseph-Bravo P (2021) Chronic stress inhibits hypothalamus-pituitary-thyroid axis and brown adipose tissue responses to acute cold exposure in male rats. J Endocrinol Invest 44(4): 713–723. https://doi.org/10.1007/s40618-020-01328-z
  13. Derkach KV, Fokina EA, Bakhtyukov AA, Sorokoumov VN, Stepochkina AM, Zakharova IO, Shpakov AO (2022) The Study of Biological Activity of a New Thieno[2,3-D]-Pyrimidine-Based Neutral Antagonist of Thyrotropin Receptor. Bull Exp Biol Med 172(6): 713–716. https://doi.org/10.1007/s10517-022-05462-x
  14. Reed HL, Silverman ED, Shakir KM, Dons R, Burman KD, O'Brian JT (1990) Changes in serum triiodothyronine (T3) kinetics after prolonged Antarctic residence: the polar T3 syndrome. J Clin Endocrinol Metab 70(4): 965–974. https://doi.org/10.1210/jcem-70-4-965
  15. Zhang Z, Boelen A, Kalsbeek A, Fliers E (2018) TRH Neurons and Thyroid Hormone Coordinate the Hypothalamic Response to Cold. Eur Thyroid J 7(6): 279–288. https://doi.org/10.1159/000493976
  16. Reed HL, Burman KD, Shakir KM, O'Brian JT (1986) Alterations in the hypothalamic-pituitary-thyroid axis after prolonged residence in Antarctica. Clin Endocrinol (Oxf) 25(1): 55–65. https://doi.org/10.1111/j.1365-2265.1986.tb03595.x
  17. Uribe RM, Zacarias M, Corkidi G, Cisneros M, Charli JL, Joseph-Bravo P (2009) 17β-Oestradiol indirectly inhibits thyrotrophin-releasing hormone expression in the hypothalamic paraventricular nucleus of female rats and blunts thyroid axis response to cold exposure. J Neuroendocrinol 21(5): 439–448. https://doi.org/10.1111/j.1365-2826.2009.01861.x
  18. Venditti P, Napolitano G, Di Stefano L, Agnisola C, Di Meo S (2011) Effect of vitamin E administration on response to ischaemia-reperfusion of hearts from cold-exposed rats. Exp Physiol 96(7): 635–646. https://doi.org/10.1113/expphysiol.2011.058289
  19. Perello M, Stuart RC, Vaslet CA, Nillni EA (2007) Cold exposure increases the biosynthesis and proteolytic processing of prothyrotropin-releasing hormone in the hypothalamic paraventricular nucleus via beta-adrenoreceptors. Endocrinology 148(10): 4952–4964. https://doi.org/10.1210/en.2007-0522
  20. Zoeller RT, Kabeer N, Albers HE (1990) Cold exposure elevates cellular levels of messenger ribonucleic acid encoding thyrotropin-releasing hormone in paraventricular nucleus despite elevated levels of thyroid hormones. Endocrinology 127(6): 2955–2962. https://doi.org/10.1210/endo-127-6-2955
  21. Sánchez E, Fekete C, Lechan RM, Joseph-Bravo P (2007) Cocaine- and amphetamine-regulated transcript (CART) expression is differentially regulated in the hypothalamic paraventricular nucleus of lactating rats exposed to suckling or cold stimulation. Brain Res 1132(1): 120–128. https://doi.org/10.1016/j.brainres.2006.11.020
  22. Uribe RM, Redondo JL, Charli JL, Joseph-Bravo P (1993) Suckling and cold stress rapidly and transiently increase TRH mRNA in the paraventricular nucleus. Neuroendocrinology 58(1): 140–145. https://doi.org/10.1159/000126523
  23. Sotelo-Rivera I, Jaimes-Hoy L, Cote-Vélez A, Espinoza-Ayala C, Charli JL, Joseph-Bravo P (2014) An acute injection of corticosterone increases thyrotrophin-releasing hormone expression in the paraventricular nucleus of the hypothalamus but interferes with the rapid hypothalamus pituitary thyroid axis response to cold in male rats. J Neuroendocrinol 26(12): 861–869. https://doi.org/10.1111/jne.12224
  24. Shpakov AO (2023) Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands. Int J Mol Sci 24(7): 6187. https://doi.org/10.3390/ijms24076187
  25. Shpakov AO (2023) Allosteric sites and allosteric regulators of G protein-coupled receptors – gray cardinals of signal transduction. J Evol Biochem Physiol 59(Suppl.1): S1–S106. https://doi.org/10.1134/S0022093023070013
  26. Neumann S, Pope A, Geras-Raaka E, Raaka BM, Bahn RS, Gershengorn MC (2012) A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts. Thyroid 22(8): 839–843. https://doi.org/10.1089/thy.2011.0520
  27. Shpakova EA, Shpakov AO, Chistyakova OV, Moyseyuk IV, Derkach KV (2012) Biological activity in vitro and in vivo of peptides corresponding to the third intracellular loop of thyrotropin receptor. Dokl Biochem Biophys 443: 64–67. https://doi.org/10.1134/S1607672912020020
  28. Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, Sobottka S, Sun H, Nazare M, Berchner-Pfannschmidt U, von Kries JP, Eckstein A, Schülein R, Krause G (2019) A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy. Thyroid 29(1): 111–123. https://doi.org/10.1089/thy.2018.0349
  29. Derkach KV, Shpakova EA, Titov AK, Shpakov AO (2015) Intranasal and Intramuscular Administration of Lysine-Palmitoylated Peptide 612–627 of Thyroid-Stimulating Hormone Receptor Increases the Level of Thyroid Hormones in Rats. Int J Pept Res Ther 21: 249–260. https://doi.org/10.1007/s10989-014-9452-6
  30. Derkach KV, Bakhtyukov AA, Sorokoumov VN, Shpakov AO (2020) New Thieno-[2,3-d]pyrimidine-Based Functional Antagonist for the Receptor of Thyroid Stimulating Hormone. Dokl Biochem Biophys 491(1): 77–80. https://doi.org/10.1134/S1607672920020064
  31. Van Heuverswyn B, Streydio C, Brocas H, Refetoff S, Dumont J, Vassart G (1984) Thyrotropin controls transcription of the thyroglobulin gene. Proc Natl Acad Sci U S A 81(19): 5941–5945. https://doi.org/10.1073/pnas.81.19.5941
  32. Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T (1997) Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves' thyroid tissue. J Clin Endocrinol Metab 82(10): 3331–3336. https://doi.org/10.1210/jcem.82.10.4269
  33. Morgan SJ, Neumann S, Marcus-Samuels B, Gershengorn MC (2016) Thyrotropin and Insulin-Like Growth Factor 1 Receptor Crosstalk Upregulates Sodium-Iodide Symporter Expression in Primary Cultures of Human Thyrocytes. Thyroid 26(12): 1794–1803. https://doi.org/10.1089/thy.2016.0323
  34. Jang D, Eliseeva E, Klubo-Gwiezdzinska J, Neumann S, Gershengorn MC (2022) TSH stimulation of human thyroglobulin and thyroid peroxidase gene transcription is partially dependent on internalization. Cell Signal 90: 110212. https://doi.org/10.1016/j.cellsig.2021.110212
  35. Jang D, Morgan SJ, Klubo-Gwiezdzinska J, Banga JP, Neumann S, Gershengorn MC (2020) Thyrotropin, but Not Thyroid-Stimulating Antibodies, Induces Biphasic Regulation of Gene Expression in Human Thyrocytes. Thyroid 30(2): 270–276. https://doi.org/10.1089/thy.2019.0418
  36. Yamada M, Monden T, Satoh T, Iizuka M, Murakami M, Iriuchijima T, Mori M (1992) Differential regulation of thyrotropin-releasing hormone receptor mRNA levels by thyroid hormone in vivo and in vitro (GH3 cells). Biochem Biophys Res Commun 184(1): 367–372. https://doi.org/10.1016/0006-291x(92)91202-2
  37. Chin WW, Carr FE, Burnside J, Darling DS (1993) Thyroid hormone regulation of thyrotropin gene expression. Recent Prog Horm Res 48: 393–414. https://doi.org/10.1016/b978-0-12-571148-7.50018-x
  38. Goulart-Silva F, de Souza PB, Nunes MT (2011) T3 rapidly modulates TSHβ mRNA stability and translational rate in the pituitary of hypothyroid rats. Mol Cell Endocrinol 332(1–2): 277–282. https://doi.org/10.1016/j.mce.2010.11.005
  39. Cyr NE, Stuart RC, Zhu X, Steiner DF, Nillni EA (2012) Biosynthesis of proTRH-derived peptides in prohormone convertase 1 and 2 knockout mice. Peptides 35(1): 42–48. https://doi.org/10.1016/j.peptides.2012.02.024
  40. Sanchez VC, Goldstein J, Stuart RC, Hovanesian V, Huo L, Munzberg H, Friedman TC, Bjorbaek C, Nillni EA (2004) Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J Clin Invest 114(3): 357–369. https://doi.org/10.1172/JCI21620
  41. Cyr NE, Toorie AM, Steger JS, Sochat MM, Hyner S, Perello M, Stuart R, Nillni EA (2013) Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH. Am J Physiol Endocrinol Metab 304(6): E640–E650. https://doi.org/10.1152/ajpendo.00448.2012

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2. Fig. 1. Expression of prothyrotropin-releasing hormone and deiodinase types 2 and 3 genes in the rat hypothalamus after prolonged cold exposure and the effect of a single treatment with TPY1 (25 mg/kg, intraperitoneally). Differences with the Control group (a) and the Cold group (b) are statistically significant at p < 0.05. M ± SEM, n = 5.

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3. Fig. 2. Expression of TRH receptor genes and β-subunit of thyroid stimulating hormone in the pituitary gland of rats after prolonged cold exposure and the effect of a single treatment with TPY1 (25 mg/kg, intraperitoneally). Differences with the Control group (a) and the Cold group (b) are statistically significant at p < 0.05. M ± SEM, n = 5.

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4. Fig. 3. Expression of thyroglobulin, sodium iodide symporter, and deiodinase types 2 and 3 genes in the rat thyroid gland after prolonged cold exposure and the effect of a single TPY1 treatment (25 mg/kg, intraperitoneally). Differences with the Control group (a) and the Cold group (b) are statistically significant at p < 0.05. M ± SEM, n = 5.

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