Modulating Effect of the Leptin Fragment 116–122 on Testicular Steroidogenesis in Male Rats

A. A. Bakhtyukov; Бахтюков А. А.; I. A. Lebedev; Лебедев И. А.; Кузнецова В. С.; K. V. Derkach; Деркач К. В.; A. O. Shpakov; Шпаков А. О.

doi:10.31857/S0869813923050023

Modulating Effect of the Leptin Fragment 116–122 on Testicular Steroidogenesis in Male Rats

Авторлар: Bakhtyukov A.¹, Lebedev I.¹, Kuznetsova В.¹, Derkach K.¹, Shpakov A.¹
Мекемелер:
1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences
Шығарылым: Том 109, № 5 (2023)
Беттер: 689-700
Бөлім: ЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИ
URL: https://journals.rcsi.science/0869-8139/article/view/137941
DOI: https://doi.org/10.31857/S0869813923050023
EDN: https://elibrary.ru/XQFQGU
ID: 137941

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат
Рұқсат жабық

Рұқсат берілді
Рұқсат жабық

Тек жазылушылар үшін

Аннотация
Авторлар туралы
Әдебиет тізімі
Қосымша файлдар
Статистика

Аннотация

Adipokine leptin plays an important role in the regulation of the reproductive system. It stimulates the activity of the hypothalamic-pituitary-gonadal axis by indirectly acting on GnRH-secreting neurons and modulates testicular steroidogenic function by binding to leptin receptors in Leydig cells. A leptin fragment 116–122 (LF) including the main receptor-binding determinants of this adipokine, normalizes metabolic parameters in animals with diet-induced obesity. However, its ability to influence the steroidogenic function of the testes, including through interaction with GnRH neurons of the hypothalamus, has not been studied. The aim of this work was to study the effects of a single and three-day intranasal administration of LF (200 μg/rat) on the blood testosterone level and the expression of steroidogenic genes in the testes in mature male Wistar rats. To evaluate the effect of LF on testicular steroidogenesis upon stimulation with human chorionic gonadotropin (hCG, 15 IU/rat, s/c), a stimulator of testosterone synthesis and an antagonist of the GnRH receptor cetrorelix (75 μg/kg, s.c.) an inhibitor of testicular steroidogenesis. It has been shown that LF increases the level of testosterone in the blood after a single injection, and after a three-day administration it enhances the steroidogenic effect of hCG. LF and hCG increased the expression of the Star gene encoding the key regulatory protein of steroidogenesis StAR. Administration of cetrorelix reduced testosterone levels and Star expression, and compensatory increased expression of the luteinizing hormone receptor gene. The potentiating effect of LF on hCG-induced stimulation of testosterone levels and Star expression was not detected under conditions of GnRH antagonist treatment. Thus, LF is capable of stimulating steroidogenesis in rat testis by itself and potentiating the steroidogenic effects of hCG. Since its effects are suppressed in the presence of a GnRH antagonist, there is reason to assume that the effect of LF is realized through stimulation of hypothalamic GnRH neurons.

Негізгі сөздер

leptin fragment, steroidogenesis, testosterone, GnRH receptor antagonist, luteinizing hormone receptor, human chorionic gonadotropin

Әдебиет тізімі

Kawwass JF, Summer R, Kallen CB (2015) Direct effects of leptin and adiponectin on peripheral reproductive tissues: a critical review. Mol Hum Reprod 21(8): 617–632. https://doi.org/10.1093/molehr/gav025
Nieuwenhuis D, Pujol-Gualdo N, Arnoldussen IAC, Kiliaan AJ (2020) Adipokines: A gear shift in puberty. Obes Rev (6): e13005. https://doi.org/10.1111/obr.13005
Childs GV, Odle AK, MacNicol MC, MacNicol AM (2021) The importance of leptin to reproduction. Endocrinology 162(2): bqaa204. https://doi.org/10.1210/endocr/bqaa204
Leisegang K, Sengupta P, Agarwal A, Henkel R (2021) Obesity and male infertility: Mechanisms and management. Andrologia 53(1): e13617. https://doi.org/10.1111/and.13617
Huang A, Roth CL (2021) The link between obesity and puberty: what is new? Curr Opin Pediatr 33(4): 449–457. https://doi.org/10.1097/MOP.0000000000001035
Obradovic M, Sudar-Milovanovic E, Soskic S, Essack M, Arya S, Stewart AJ, Gojobori T, Isenovic ER (2021) Leptin and obesity: role and clinical implication. Front Endocrinol (Lausanne) 12: 585887. https://doi.org/10.3389/fendo.2021.585887
Novakovic ZM, Leinung MC, Lee DW, Grasso P (2009) Intranasal administration of mouse [D-Leu-4]OB3, a synthetic peptide amide with leptin-like activity, enhances total uptake and bioavailability in Swiss Webster mice when compared to intraperitoneal, subcutaneous, and intramuscular delivery systems. Regul Pept 154(1–3): 107–111. https://doi.org/10.1016/j.regpep.2009.01.002
Novakovic ZM, Leinung MC, Grasso P (2013) [D-Leu-4]-OB3, an orally bioavailable leptin-related synthetic peptide insulin sensitizer: a study comparing the efficacies of [D-Leu-4]-OB3 and metformin on energy balance and glycemic regulation in insulin-deficient male Swiss Webster mice. Peptides 43: 167–173. https://doi.org/10.1016/j.peptides.2013.02.023
Leinung MC, Grasso P (2012) [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, augments the effects of orally delivered exenatide and pramlintide acetate on energy balance and glycemic control in insulin-resistant male C57BLK/6-m db/db mice. Regul Pept 179(1–3): 33–38. https://doi.org/10.1016/j.regpep.2012.08.006
Wang A, Anderson BM, Novakovic ZM, Grasso P (2018) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice. Peptides 101: 51–59. https://doi.org/10.1016/j.peptides.2017.12.012
Bakhtyukov AA, Derkach KV, Sorokoumov VN, Stepochkina AM, Romanova IV, Morina IY, Zakharova IO, Bayunova LV, Shpakov AO (2022) The effects of separate and combined treatment of male rats with type 2 diabetes with metformin and orthosteric and allosteric agonists of luteinizing hormone receptor on steroidogenesis and spermatogenesis. Int J Mol Sci 23(1): 198. https://doi.org/10.3390/ijms23010198
Anderson BM, Jacobson L, Novakovic ZM, Grasso P (2017) Oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, synthetic peptide leptin mimetics: Immunofluorescent localization in the mouse hypothalamus. Brain Res 1664: 1–8. https://doi.org/10.1016/j.brainres.2017.03.020
Derkach KV, Bakhtyukov AA, Morina IY, Romanova IV, Bayunova LV, Shpakov AO (2022) Comparative study of the restoring effect of metformin, gonadotropin, and allosteric agonist of luteinizing hormone receptor on spermatogenesis in male rats with streptozotocin-induced type 2 diabetes mellitus. Bull Exp Biol Med 172(4): 435–440. https://doi.org/10.1007/s10517-022-05409-2
Derkach KV, Bakhtyukov AA, Bayunova LV, Zorina II, Shpakov AO (2020) Normalization of testicular steroidogenesis and spermatogenesis in male rats with type 2 diabetes mellitus under the conditions of metformin therapy. Dokl Biol Sci 493(1): 110–113. https://doi.org/10.1134/S0012496620040031
Zirkin BR, Papadopoulos V (2018) Leydig cells: formation, function, and regulation. Biol Reprod 99(1): 101–111. https://doi.org/10.1093/biolre/ioy059
Reissmann T, Schally AV, Bouchard P, Riethmiiller H, Engel J (2000) The LHRH antagonist cetrorelix: a review. Hum Reprod Update 6(4): 322–331. https://doi.org/10.1093/humupd/6.4.322