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The thyroid status of rats immunized with peptides derived from the extracellular regions of the types 3 and 4 melanocortin receptors and the 1B-subtype 5-hydroxytryptamine receptor

  • Comparative and Ontogenic Biochemistry
  • Published:
Journal of Evolutionary Biochemistry and Physiology Aims and scope Submit manuscript

Abstract

Activity of the hypothalamic–pituitary–thyroid (HPT) axis is controlled by the brain neurotransmitter systems, including the melanocortin signaling system. Pharmacological inhibition of type 4 melanocortin receptors (M4R) leads to disruption of the HPT axis function and reduction in the level of thyroid hormones. At the same time, the data on how a prolonged M4R inhibition affects this axis and on the role of these receptors in regulation of this axis are absent. The relationship between thyroid status and the activity of 1B-subtype 5-hydroxytryptamine receptor (5-HT1BR) is scarcely explored. The aim of this work was to study the effects of chronic M3R, M4R and 5-HT1BR inhibition induced by immunization of rats with BSA-conjugated peptides derived from the extracellular regions of these receptors on thyroid status and the activity of thyroid stimulating hormone (TSH)-sensitive adenylyl cyclase signaling system (ACSS) in the thyroid gland (TG) of immunized animals. In rats immunized with peptides K-[TSLHLWNRSSHGLHG11–25]-A (M4R), A-[PTNPYCICTTAH269–280]-A (M3R) and [QAKAEEEVSEC(Acm)-VVNTDH189–205]-A (5-HT1BR), the levels of thyroid hormones, such as fT4, tT4 and tT3, were significantly reduced. In rats immunized with M4R and M3R peptides, the TSH level increased, while in animals immunized with 5-HT1BR peptide, on the contrary, it was reduced. In the TG of rats immunized with M4R and M3R peptides, the stimulatory effects of hormones (TSH, PACAP-38) and GppNHp on the adenylyl cyclase activity were attenuated, and changes were most pronounced for M4R peptide immunization. After immunization with 5-HT1BR peptide, the stimulatory effects of TSH, PACAP-38 and GppNHp persisted. Thus, the main cause of thyroid hormone deficiency in rats immunized with M4R and M3R peptides was the decreased sensitivity of thyrocitic ACSS to TSH, whereas in rats immunized with 5-HT1BR peptide thyroid hormone deficiency was due to the decreased level of TSH. Our data on the negative impact of long-term immunization of rats with BSA-conjugated peptides derived from the extracellular regions of M4R, M3R and 5-HT1BR on their thyroid status provide a strong argument in favor of the involvement of these receptors and receptor-coupled intracellular signaling pathways in the regulation of the HPT axis.

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Abbreviations

te]ALP:

Agouti-like peptide

AC:

adenylyl cyclase

ACSS:

adenylyl cyclase signaling system

BSA:

bovine serum albumin

HPT axis:

hypothalamic–pituitary–thyroid axis

M3R and M4R:

type 3 and 4 melanocortin receptors

α-MSH and γ-MSH:

α- and γ-melanocytestimulating hormones

TSH:

thyroid stimulating hormone

TFAA:

trifluoroacetic acid

TG:

thyroid gland

fT4 :

free thyroxine

tT4 :

total thyroxine

tT3 :

total triiodothyronine

HOMA-IR:

homeostasis model assessment-insulin resistance

PACAP-38:

pituitary adenylyl cyclase-activating polypeptide-38

References

  1. Zoeller, R.T., Tan, S.W., and Tyl, R.W., General background on the hypothalamic–pituitary–thyroid (HPT) axis, Crit. Rev. Toxicol., 2007, vol. 37, pp. 11–53.

    Article  CAS  PubMed  Google Scholar 

  2. Claus, M., Neumann, S., Kleinau, G., Krause, G., and Paschke, R., Structural determinants for G-protein activation and specificity in the third intracellular loop of the thyroid-stimulating hormone receptor, J. Mol. Med. (Berl.), 2006, vol. 84, pp. 943–954.

    Article  CAS  Google Scholar 

  3. Shpakov, A.O., Structural-functional organization of polypeptide hormone receptors containing LRR-repeats and their interaction with heterotrimeric G-proteins, Tsitol., 2009, vol. 51, no. 8, pp. 637–649.

    CAS  Google Scholar 

  4. Kleinau, G., Jaeschke, H., Worth, C.L., Mueller, S., Gonzalez, J., Paschke, R., and Krause, G., Principles and determinants of G-protein coupling by the rhodopsin-like thyrotropin receptor, PLoS One, 2010, vol. 5, e9745. doi: 10.1371/journal.pone.0009745.

    Article  Google Scholar 

  5. Nillni, E.A., Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs, Front. Neuroendocrinol., 2010, vol. 31, pp. 134–156.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Costa-e-Sousa, R.H. and Hollenberg, A.N., Minireview: The neural regulation of the hypothalamic–pituitary–thyroid axis, Endocrinology, 2012, vol. 153, pp. 4128–4135.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Lechan, R.M. and Fekete, C., Role of melanocortin signaling in the regulation of the hypothalamic–pituitary–thyroid (HPT) axis, Peptides, 2006, vol. 27, pp. 310–325.

    Article  CAS  PubMed  Google Scholar 

  8. Martin, N.M., Smith, K.L., Bloom, S.R., and Small, C.J., Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis, Peptides, 2006, vol. 27, pp. 333–339.

    Article  CAS  PubMed  Google Scholar 

  9. Kim, M.S., Small, C.J., Stanley, S.A., Morgan, D.G., Seal, L.J., Kong, W.M., Edwards, C.M., Abusnana, S., Sunter, D., Ghatei, M.A., and Bloom, S.R., The central melanocortin system affects the hypothalamo–pituitary thyroid axis and may mediate the effect of leptin, J. Clin. Invest., 2000, vol. 105, pp. 1005–1011.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Fekete, C., Marks, D.L., Sarkar, S., Emerson, C.H., Rand, W.M., Cone, R.D., and Lechan, R.M., Effect of Agouti-related protein in regulation of the hypothalamic–pituitary–thyroid axis in the melanocortin 4 receptor knockout mouse, Endocrinology, 2004, vol. 145, pp. 4816–4821.

    Article  CAS  PubMed  Google Scholar 

  11. Preston, E., Cooney, G.J., Wilks, D., Baran, K., Zhang, L., Kraegen, E.W., and Sainsbury, A., Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways, Neuropeptides, 2011, vol. 45, pp. 407–415.

    Article  CAS  PubMed  Google Scholar 

  12. Renquist, B.J., Lippert, R.N., Sebag, J.A., Ellacott, K.L., and Cone, R.D., Physiological roles of the melanocortin MC3 receptor, Eur. J. Pharmacol., 2011, vol. 660, pp. 13–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Bauer, M., Heinz, A., and Whybrow, P.C., Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain, Mol. Psychiatry, 2002, vol. 7, pp. 140–156.

    Article  CAS  PubMed  Google Scholar 

  14. Lifschytz, T., Gur, E., Lerer, B., and Newman, M.E., Effects of triiodothyronine and fluoxetine on 5-HT1A and 5-HT1B autoreceptor activity in rat brain: regional differences, J. Neurosci. Methods, 2004, vol. 140, pp. 133–139.

    Article  CAS  PubMed  Google Scholar 

  15. Shpakova, E.A., Derkach, K.V., and Shpakov, A.O., Effect of peptides derived from the extracellular regions of subtype 1B/1D 5-hydroxytryptamine receptor and types 3 and 4 melanocortin receptors on the adenylyl cyclase hormonal regulation in rat brain, Bull. Exp. Biol. Med., 2013, vol. 156, no. 11, pp. 603–607.

    Google Scholar 

  16. Shpakova, E.A., Shpakov, A.O., Chistyakova, O.V., Moiseyuk, I.V., and Derkach, K.V., Biological in vitro and in vivo activity of peptides corresponding to the third cytoplasmic loop of thyrotropin receptor, Dokl. Akad. Nauk, 2012, vol. 443, vol. 1, pp. 123–126.

    Google Scholar 

  17. Shpakov, A.O., Shpakova, E.A., Tarasenko, I.I., Derkach, K.V., and Vlasov, G.P., The peptides mimicking the third intracellular loop of 5-hydroxytryptamine receptors of the types 1B and 6 selectively activate G proteins and receptor-specifically inhibit serotonin signaling via the adenylyl cyclase system, Int. J. Pept. Res. Ther., 2010, vol. 16, pp. 95–105.

    Article  CAS  Google Scholar 

  18. Derkach, K.V., Shpakova, E.A., Titov, A.M., and Shpakov, A.O., 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., 2015, vol. 21, DOI: 10.1007/s10989-014-9452-6.

  19. Shpakov, A.O., Chistyakova, O.V., Derkach, K.V., Moiseyuk, I.V., and Bondareva, V.M., Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes, Central Eur. J. Biol., 2012, vol. 7, no. 1, pp. 33–47.

    CAS  Google Scholar 

  20. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., and Turner, R.C., Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man, Diabetologia, 1985, vol. 28, pp. 412–419.

    Article  CAS  PubMed  Google Scholar 

  21. Small, C.J., Kim, M.S., Stanley, S.A., Mitchell, J.R., Murphy, K., Morgan, D.G., Ghatei, M.A., and Bloom, S.R., Effects of chronic central nervous system administration of agoutirelated protein in pair-fed animals, Diabetes, 2001, vol. 50, pp. 248–254.

    Article  CAS  PubMed  Google Scholar 

  22. Dutia, R., Kim, A.J., Modes, M., Rothlein, R., Shen, J.M., Tian, Y.E., Ihbais, J., Victory, S.F., Valcarce, C., and Wardlaw, S.L., Effects of AgRP inhibition on energy balance and metabolism in rodent models, PLoS One, 2013, vol. 8,: e65317. doi: 10.1371/journal.pone.0065317.

    Article  Google Scholar 

  23. Krude, H., Biebermann, H., Schnabel, D., Tansek, M.Z., Theunissen, P., Mullis, P.E., and Grüters, A., Obesity due to proopiomelanocortin deficiency: three new cases and treatment trials with thyroid hormone and ACTH4–10, J. Clin. Endocrinol. Metab., 2003, vol. 88, pp. 4633–4640.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences, 194223, St. Petersburg, Russia

    K. V. Derkach, I. V. Moiseyuk & A. O. Shpakov

  2. Institute of Macromolecular Compounds of Russian Academy of Sciences, St. Petersburg, Russia

    E. A. Shpakova

Authors
  1. K. V. Derkach
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  2. I. V. Moiseyuk
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  3. E. A. Shpakova
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  4. A. O. Shpakov
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Correspondence to A. O. Shpakov.

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Original Russian Text © K.V. Derkach, I.V. Moiseyuk, E.A. Shpakova, A.O. Shpakov, 2015, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2015, Vol. 51, No. 4, pp. 243—250.

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Derkach, K.V., Moiseyuk, I.V., Shpakova, E.A. et al. The thyroid status of rats immunized with peptides derived from the extracellular regions of the types 3 and 4 melanocortin receptors and the 1B-subtype 5-hydroxytryptamine receptor. J Evol Biochem Phys 51, 279–287 (2015). https://doi.org/10.1134/S0022093015040031

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  • DOI: https://doi.org/10.1134/S0022093015040031

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