actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2019-4.3.1actabiomedica-2079Research ArticleАКУШЕРСТВО И ГИНЕКОЛОГИЯOBSTETRICS AND GYNAECOLOGYРоль апелина в функционировании репродуктивной системыThe Role of Apelin in the Functioning of the Reproductive Systemhttps://orcid.org/0000-0002-4293-3162ШпаковА. О.ShpakovA. O.

Шпаков Александр Олегович – доктор биологических наук, заведующий лабораторией молекулярной эндокринологии и нейрохимии

ID: 35231150500, РИНЦ SPIN-код: 6335-8311, Author ID: 87662

194223, г. Санкт-Петербург, пр. Тореза, 44

Aleksandr O. Shpakov – Dr. Sc. (Biol.), Head of the Laboratory of Molecular Endocrinology and Neurochemistry

pr. Toreza 44, Saint Petersburg, 194223

SCOPUS ID: 35231150500, RSCI SPIN Code: 6335-8311, Author ID: 87662

alex_shpakov@list.ruhttps://orcid.org/0000-0001-6555-9540ДеркачК. В.DerkachK. V.

Деркач Кира Викторовна – кандидат биологических наук, ведущий научный сотрудник лаборатории молекулярной эндокринологии и нейрохимии

SCOPUS ID: 6603743572; РИНЦ SPIN-код: 6925-1558; Author ID: 83183

194223, г. Санкт-Петербург, пр. Тореза, 44

Kira V. Derkach – Cand. Sc. (Biol.), Senior Research Officer at the Laboratory of Molecular Endocrinology and Neurochemistry

pr. Toreza 44, Saint Petersburg, 194223

SCOPUS ID: 6603743572; RSCI SPIN Code: 6925-1558; Author ID: 83183

ФГБУН Институт эволюционной физиологии и биохимии им. И.М. Сеченова РАНSechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences20191107201943717Copyright © Шпаков А.О., Деркач К.В., 20192019Шпаков А.О., Деркач К.В.Shpakov A.O., Derkach K.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/2079

Адипокин апелин посредством апелиновых рецепторов активирует широкий спектр сигнальных каскадов в клетках-мишенях и контролирует их рост, дифференцировку, апоптоз, энергетический обмен. В последние годы получены доказательства того, что мишенями апелина являются все компоненты гипоталамо-гипофизарно-гонадной оси, на что указывает экспрессия в них апелина и его рецептора. В гипоталамусе апелин модулирует активность меланокортиновой и грелиновой систем и опосредованно влияет на продукцию гонадолиберина. В яичниках он контролирует рост и созревание фолликулов, стимулирует ангиогенез, влияет на базальную и стимулированную другими факторами стероидогенную активность фолликулярных клеток. Изменения в апелиновой сигнальной системе тесно связаны с такими дисфункциями женской репродуктивной системы, как синдром поликистозных яичников, эндометриоз, рак. Информация о регуляции мужской репродуктивной системы апелином ограничивается исследованиями на животных, свидетельствующими о влиянии апелина на гипоталамические звенья гонадной оси. Участие апелина в регуляции репродуктивной системы открывает широкие возможности для разработки на его основе новых подходов для коррекции нарушений в этой системе и лечения бесплодия.

Adipokine apelin through the apelin receptors activates a wide range of signaling cascades in the target cells and controls their growth, differentiation, apoptosis, and energy metabolism. In the recent years, the evidence has been obtained that all components of the hypothalamic-pituitary-gonad axis, in which apelin and its receptor are expressed, are targets of apelin. In the hypothalamus, apelin modulates the activity of the melanocortin and ghrelin systems and indirectly affects the production of gonadoliberin. In the ovaries, it controls the growth and maturation of the follicles, stimulates the angiogenesis, and affects the basal and stimulated by the other factors steroidogenic activity in follicular cells. The changes in the apelin signaling system are closely associated with dysfunctions of the female reproductive system, such as polycystic ovary syndrome, endometriosis, and cancer. Information on the regulation of the male reproductive system by apelin is limited to animal studies showing the effect of apelin on the hypothalamic components of the gonad axis. The participation of apelin in the regulation of the reproductive system opens up the broad opportunities for the development of new approaches for the correction of abnormalities in this system and for the treatment of infertility.

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Biol Reprod. 2016; 95(5): 104. doi: 10.1095/biolreprod.116.141754Picault FX, Chaves-Almagro C, Projetti F, Prats H, Masri B, Audigier Y. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur J Cancer. 2014; 50(3): 663-674. doi: 10.1016/j.ejca.2013.11.017Schilffarth S, Antoni B, Schams D, Meyer HH, Berisha B. The expression of apelin and its receptor APJ during different physiological stages in the bovine ovary. Int J Biol Sci. 2009; 5(4): 344-350. doi: 10.7150/ijbs.5.344.Sandal S, Tekin S, Seker FB, Beytur A, Vardi N, Colak C, et al. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats. Neurosci Lett. 2015; 602: 133-138. doi: 10.1016/j.neulet.2015.06.059Schilffarth S, Antoni B, Schams D, Meyer HH, Berisha B. The expression of apelin and its receptor APJ during different physiological stages in the bovine ovary. Int J Biol Sci. 2009; 5(4): 344-350. doi: 10.7150/ijbs.5.344.Tekin S, Erden Y, Sandal S, Etem Onalan E, Ozyalin F, Ozen H, et al. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch Physiol Biochem. 2017; 123(1): 9-15. doi: 10.1080/13813455.2016.1211709Rak A, Drwal E, Rame C, Knapczyk-Stwora K, Słomczyńska M, Dupont J, et al. Expression of apelin and apelin receptor (APJ) in porcine ovarian follicles and in vitro effect of apelin on steroidogenesis and proliferation through APJ activation and different signaling pathways. Theriogenology. 2017; 96: 126-135. doi: 10.1016/j.theriogenology.2017.04.014.Medhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84(5): 1162-1172. doi: 10.1046/j.1471-4159.2003.01587.xRak A, Drwal E, Rame C, Knapczyk-Stwora K, Słomczyńska M, Dupont J, et al. Expression of apelin and apelin receptor (APJ) in porcine ovarian follicles and in vitro effect of apelin on steroidogenesis and proliferation through APJ activation and different signaling pathways. Theriogenology. 2017; 96: 126-135. doi: 10.1016/j.theriogenology.2017.04.014.Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides. 2012; 33(1): 139-148. doi: 10.1016/j.peptides.2011.12.005Roche J, Ramé C, Reverchon M, Mellouk N, Rak A, Froment P, et al. Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. Reproduction. 2017; 153(5): 589-603. doi: 10.1530/REP-16-0677Roche J, Ramé C, Reverchon M, Mellouk N, Rak A, Froment P, et al. Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. Reproduction. 2017; 153(5): 589-603. doi: 10.1530/REP-16-0677Roche J, Ramé C, Reverchon M, Mellouk N, Rak A, Froment P, et al. Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. Reproduction. 2017; 153(5): 589-603. doi: 10.1530/REP-16-0677Shuang L, Jidong W, Hongjuan P, Zhenwei Y. Effects of apelin on proliferation and apoptosis in rat ovarian granulosa cells. Clin Exp Obst Gynecol. 2016; 43(3): 409-413.Shuang L, Jidong W, Hongjuan P, Zhenwei Y. Effects of apelin on proliferation and apoptosis in rat ovarian granulosa cells. Clin Exp Obst Gynecol. 2016; 43(3): 409-413.Shuang L, Jidong W, Hongjuan P, Zhenwei Y. Effects of apelin on proliferation and apoptosis in rat ovarian granulosa cells. Clin Exp Obst Gynecol. 2016; 43(3): 409-413.Shuang L, Jidong W, Hongjuan P, Zhenwei Y. Effects of apelin on proliferation and apoptosis in rat ovarian granulosa cells. Clin Exp Obst Gynecol. 2016; 43(3): 409-413.Altinkaya SÖ, Nergiz S, Küçük M, Yüksel H. Apelin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur J Obst Gynecol Reprod Biol. 2014; 176: 168-172. doi: 10.1016/j.ejogrb.2014.02.022Altinkaya SÖ, Nergiz S, Küçük M, Yüksel H. Apelin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur J Obst Gynecol Reprod Biol. 2014; 176: 168-172. doi: 10.1016/j.ejogrb.2014.02.022Altinkaya SÖ, Nergiz S, Küçük M, Yüksel H. Apelin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur J Obst Gynecol Reprod Biol. 2014; 176: 168-172. doi: 10.1016/j.ejogrb.2014.02.022Altinkaya SÖ, Nergiz S, Küçük M, Yüksel H. Apelin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome. Eur J Obst Gynecol Reprod Biol. 2014; 176: 168-172. doi: 10.1016/j.ejogrb.2014.02.022Chang CY, Tsai YC, Lee CH, Chan TF, Wang SH, Su JH. Lower serum apelin levels in women with polycystic ovary syndrome. Fert Steril. 2011; 95(8): 2520-2523. doi: 10.1016/j.fertnstert.2011.04.044Chang CY, Tsai YC, Lee CH, Chan TF, Wang SH, Su JH. Lower serum apelin levels in women with polycystic ovary syndrome. Fert Steril. 2011; 95(8): 2520-2523. doi: 10.1016/j.fertnstert.2011.04.044Chang CY, Tsai YC, Lee CH, Chan TF, Wang SH, Su JH. Lower serum apelin levels in women with polycystic ovary syndrome. Fert Steril. 2011; 95(8): 2520-2523. doi: 10.1016/j.fertnstert.2011.04.044Chang CY, Tsai YC, Lee CH, Chan TF, Wang SH, Su JH. Lower serum apelin levels in women with polycystic ovary syndrome. Fert Steril. 2011; 95(8): 2520-2523. doi: 10.1016/j.fertnstert.2011.04.044Gören K, Sağsöz N, Noyan V, Yücel A, Cağlayan O, Bostancı MS. Plasma apelin levels in patients with polycystic ovary syndrome. J Turk Germ Gynecol Assoc. 2012; 13(1): 27-31. doi: 10.5152/jtgga.2011.74Gören K, Sağsöz N, Noyan V, Yücel A, Cağlayan O, Bostancı MS. Plasma apelin levels in patients with polycystic ovary syndrome. J Turk Germ Gynecol Assoc. 2012; 13(1): 27-31. doi: 10.5152/jtgga.2011.74Gören K, Sağsöz N, Noyan V, Yücel A, Cağlayan O, Bostancı MS. Plasma apelin levels in patients with polycystic ovary syndrome. J Turk Germ Gynecol Assoc. 2012; 13(1): 27-31. doi: 10.5152/jtgga.2011.74Gören K, Sağsöz N, Noyan V, Yücel A, Cağlayan O, Bostancı MS. Plasma apelin levels in patients with polycystic ovary syndrome. J Turk Germ Gynecol Assoc. 2012; 13(1): 27-31. doi: 10.5152/jtgga.2011.74Olszanecka-Glinianowicz M, Madej P, Nylec M, Owczarek A, Szanecki W, Skałba P, et al. Circulating apelin level in relation to nutritional status in polycystic ovary syndrome and its association with metabolic and hormonal disturbances. Clin Endocrinol. 2013; 79(2): 238-242. doi: 10.1111/cen.12120Olszanecka-Glinianowicz M, Madej P, Nylec M, Owczarek A, Szanecki W, Skałba P, et al. Circulating apelin level in relation to nutritional status in polycystic ovary syndrome and its association with metabolic and hormonal disturbances. Clin Endocrinol. 2013; 79(2): 238-242. doi: 10.1111/cen.12120Olszanecka-Glinianowicz M, Madej P, Nylec M, Owczarek A, Szanecki W, Skałba P, et al. Circulating apelin level in relation to nutritional status in polycystic ovary syndrome and its association with metabolic and hormonal disturbances. Clin Endocrinol. 2013; 79(2): 238-242. doi: 10.1111/cen.12120Olszanecka-Glinianowicz M, Madej P, Nylec M, Owczarek A, Szanecki W, Skałba P, et al. Circulating apelin level in relation to nutritional status in polycystic ovary syndrome and its association with metabolic and hormonal disturbances. Clin Endocrinol. 2013; 79(2): 238-242. doi: 10.1111/cen.12120Sun X, Wu X, Zhou Y, Yu X, Zhang W. Evaluation of apelin and insulin resistance in patients with PCOS and therapeutic effect of drospirenone-ethinylestradiol plus metformin. Med Sci Monitor. 2015; 21: 2547-2552. doi: 10.12659/MSM.894926Sun X, Wu X, Zhou Y, Yu X, Zhang W. Evaluation of apelin and insulin resistance in patients with PCOS and therapeutic effect of drospirenone-ethinylestradiol plus metformin. Med Sci Monitor. 2015; 21: 2547-2552. doi: 10.12659/MSM.894926Sun X, Wu X, Zhou Y, Yu X, Zhang W. Evaluation of apelin and insulin resistance in patients with PCOS and therapeutic effect of drospirenone-ethinylestradiol plus metformin. Med Sci Monitor. 2015; 21: 2547-2552. doi: 10.12659/MSM.894926Sun X, Wu X, Zhou Y, Yu X, Zhang W. Evaluation of apelin and insulin resistance in patients with PCOS and therapeutic effect of drospirenone-ethinylestradiol plus metformin. Med Sci Monitor. 2015; 21: 2547-2552. doi: 10.12659/MSM.894926Ozkan ZS, Cilgin H, Simsek M, Cobanoglu B, Ilhan N. Investigation of apelin expression in endometriosis. J Reprod Infert. 2013; 14(2): 50–55.Ozkan ZS, Cilgin H, Simsek M, Cobanoglu B, Ilhan N. Investigation of apelin expression in endometriosis. J Reprod Infert. 2013; 14(2): 50–55.Ozkan ZS, Cilgin H, Simsek M, Cobanoglu B, Ilhan N. Investigation of apelin expression in endometriosis. J Reprod Infert. 2013; 14(2): 50–55.Ozkan ZS, Cilgin H, Simsek M, Cobanoglu B, Ilhan N. Investigation of apelin expression in endometriosis. J Reprod Infert. 2013; 14(2): 50–55.Hoffmann M, Fiedor E, Ptak A. Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett. 2017; 269: 15-22. doi: 10.1016/j.toxlet.2017.01.006Hoffmann M, Fiedor E, Ptak A. Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett. 2017; 269: 15-22. doi: 10.1016/j.toxlet.2017.01.006Hoffmann M, Fiedor E, Ptak A. Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett. 2017; 269: 15-22. doi: 10.1016/j.toxlet.2017.01.006Hoffmann M, Fiedor E, Ptak A. Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett. 2017; 269: 15-22. doi: 10.1016/j.toxlet.2017.01.006Picault FX, Chaves-Almagro C, Projetti F, Prats H, Masri B, Audigier Y. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur J Cancer. 2014; 50(3): 663-674. doi: 10.1016/j.ejca.2013.11.017Picault FX, Chaves-Almagro C, Projetti F, Prats H, Masri B, Audigier Y. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur J Cancer. 2014; 50(3): 663-674. doi: 10.1016/j.ejca.2013.11.017Picault FX, Chaves-Almagro C, Projetti F, Prats H, Masri B, Audigier Y. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur J Cancer. 2014; 50(3): 663-674. doi: 10.1016/j.ejca.2013.11.017Picault FX, Chaves-Almagro C, Projetti F, Prats H, Masri B, Audigier Y. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur J Cancer. 2014; 50(3): 663-674. doi: 10.1016/j.ejca.2013.11.017Sandal S, Tekin S, Seker FB, Beytur A, Vardi N, Colak C, et al. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats. Neurosci Lett. 2015; 602: 133-138. doi: 10.1016/j.neulet.2015.06.059Sandal S, Tekin S, Seker FB, Beytur A, Vardi N, Colak C, et al. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats. Neurosci Lett. 2015; 602: 133-138. doi: 10.1016/j.neulet.2015.06.059Sandal S, Tekin S, Seker FB, Beytur A, Vardi N, Colak C, et al. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats. Neurosci Lett. 2015; 602: 133-138. doi: 10.1016/j.neulet.2015.06.059Sandal S, Tekin S, Seker FB, Beytur A, Vardi N, Colak C, et al. The effects of intracerebroventricular infusion of apelin-13 on reproductive function in male rats. Neurosci Lett. 2015; 602: 133-138. doi: 10.1016/j.neulet.2015.06.059Tekin S, Erden Y, Sandal S, Etem Onalan E, Ozyalin F, Ozen H, et al. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch Physiol Biochem. 2017; 123(1): 9-15. doi:10.1080/13813455.2016.1211709Tekin S, Erden Y, Sandal S, Etem Onalan E, Ozyalin F, Ozen H, et al. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch Physiol Biochem. 2017; 123(1): 9-15. doi:10.1080/13813455.2016.1211709Tekin S, Erden Y, Sandal S, Etem Onalan E, Ozyalin F, Ozen H, et al. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch Physiol Biochem. 2017; 123(1): 9-15. doi:10.1080/13813455.2016.1211709Tekin S, Erden Y, Sandal S, Etem Onalan E, Ozyalin F, Ozen H, et al. Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. Arch Physiol Biochem. 2017; 123(1): 9-15. doi:10.1080/13813455.2016.1211709Medhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84(5): 1162-1172. doi: 10.1046/j.1471-4159.2003.01587.xMedhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84(5): 1162-1172. doi: 10.1046/j.1471-4159.2003.01587.xMedhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84(5): 1162-1172. doi: 10.1046/j.1471-4159.2003.01587.xMedhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84(5): 1162-1172. doi: 10.1046/j.1471-4159.2003.01587.xPope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides. 2012; 33(1): 139-148. doi: 10.1016/j.peptides.2011.12.005Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides. 2012; 33(1): 139-148. doi: 10.1016/j.peptides.2011.12.005Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides. 2012; 33(1): 139-148. doi: 10.1016/j.peptides.2011.12.005Pope GR, Roberts EM, Lolait SJ, O’Carroll AM. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides. 2012; 33(1): 139-148. doi: 10.1016/j.peptides.2011.12.005

The authors declare that there are no conflicts of interest present.