НОВЫЕ ДОСТИЖЕНИЯ В ИЗУЧЕНИИ ЭНДОГЕННЫХ РЕГУЛЯТОРОВ СИНТЕЗА И СЕКРЕЦИИ ГОНАДОТРОПИНОВ
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Ключевые слова

гонадотропин, гипоталамо-гипофизарно-гонадная ось, гонадотропин-ингибирующий гормон, активин, ингибин, лептин, адипонектин

Как цитировать

[1]
К. В. Деркач и А. О. Шпаков, «НОВЫЕ ДОСТИЖЕНИЯ В ИЗУЧЕНИИ ЭНДОГЕННЫХ РЕГУЛЯТОРОВ СИНТЕЗА И СЕКРЕЦИИ ГОНАДОТРОПИНОВ», Рос. физиол. журн. им. И. М. Сеченова, т. 104, вып. 12, дек. 2018.

Аннотация

Гонадотропины — лютеинизирующий (ЛГ) и фолликулостимулирующий гормоны (ФСГ) — являются ключевыми регуляторами гипоталаламо-гипофизарно-гонадной оси. Их синтез и секреция контролируются гонадолиберином, гипоталамическим рилизинг-фактором. Однако в последние годы все большее внимание приковано к другим регуляторам продукции гонадотропинов — гонадотропин-ингибирующему гормону, активинам, ингибинам, фоллистатину. Наряду с этим показано, что синтез и секреция гонадотропинов могут контролироваться адипокинами — лептином и его функциональным антагонистом адипонектином, которые осуществляют тесную взаимосвязь между энергетическим балансом и функциональным состоянием репродуктивной системы. Адипокины регулируют продукцию гонадотропинов как через гипоталамические механизмы, так и непосредственно воздействуя на гонадотрофы гипофиза. В обзоре рассмотрены современные достижения в области изучения регуляторного влияния и механизмов действия гонадотропин-ингибирующего гормона, активинов, ингибинов, фоллистатина, лептина и адипонектина на продукцию гонадотропинов и зависимые от них репродуктивные функции.

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Литература

Шпаков А. О. Гликозилирование гонадтропинов как важнейший механизм регуляции их активности. Рос. физиол. журн. им. И. М. Сеченова. 103 (9): 1004—1021. 2017. [Shpakov A. O. Glycosilation of gonadotropis, as the most important mechanism of regulation of their activity. Rus. J. Physiol. 103 (9): 1004—1017. (In Russ.)].

Plant T. M. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary-gonadal axis. J. Endocrinol. 226 (2): T41—T54. 2015.

Maeda K., Ohkura S., Uenoyama Y., Wakabayashi Y., Oka Y., Tsukamura H., Okamura H. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. 1364: 103—115. 2010.

Ezzat A., Pereira A., Clarke I. J. Kisspeptin is a component of the pulse generator for gonadotropin releasing hormone (GnRH) secretion in female sheep but not THE pulse generator. Endocrinology. 156 (5): 1828—1837. 2015.

Hrabovszky E., Ciofi P., Vida B., Horvath M. C., Keller E., Caraty A., Bloom S. R., Ghatei M. A., Dhillo W. S., Liposits Z., Kallo I. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur. J. Neurosci. 31 (11): 1984—1998. 2010.

Messager S., Chatzidaki E. E., Ma D., Hendrick A. G., Zahn D., Dixon J., Thresher R. R., Malinge I., Lomet D., Carlton M. B., Colledge W. H., Caraty A., Aparicio S. A. Kisspeptin directly stimulates gonadotropinreleasing hormone release via G protein-coupled receptor 54. Proc. Natl. Acad. Sci. USA. 102 (5): 1761—1766. 2005.

Navarro V. M., Castellano J. M., Fernandez-Fernandez R., Barreiro M. L., Roa J., Sanchez-Criado J. E., Aguilar E., Dieguez C., Pinilla L., Tena-Sempere M. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS—1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS—1 peptide. Endocrinology. 145 (10): 4565—4574. 2004.

Shahab M., Mastronardi C., Seminara S. B., Crowley W. F., Ojeda S. R., Plant T. M. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc. Natl. Acad. Sci. USA. 102 (6): 2129—2134. 2005.

Tsutsui K., Saigoh E., Ukena K., Teranishi H., Fujisawa Y., Kikuchi M., Ishii S., Sharp P. J. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem. Biophys. Res. Commun. 275 (2): 661—667. 2000.

Iwasa T., Matsuzaki T., Yano K., Irahara M. Gonadotropin-inhibitory hormone plays roles in stress-induced reproductive dysfunction. Front. Endocrinol. (Lausanne). 8: 62. 2017.

Tsutsui K., Ubuka T., Bentley G. E., Kriegsfeld L. J. Gonadotropin-inhibitory hormone (GnIH): discovery, progress and prospect. Gen. Comp. Endocrinol. 177 (3): 305—314. 2012.

Ukena K., Ubuka T., Tsutsui K. Distribution of a novel avian gonadotropininhibitory hormone in the quail brain. Cell Tissue Res. 312 (1): 73—79. 2003.

Tsutsui K., Ubuka T. GnIH control of feeding and reproductive behaviors. Front. Endocrinol. 7: 170. 2016.

McGuire N. L., Bentley G. E. Neuropeptides in the gonads: from evolution to pharmacology. Front. Pharmacol. 1: 114. 2010.

Zhao S., Zhu E., Yang C., Bentley G. E., Tsutsui K., Kriegsfeld L. J. RFamide-related peptide and messenger ribonucleic acid expression in mammalian testis: association with the spermatogenic cycle. Endocrinology. 151 (2): 617—627. 2010.

Gibson E. M., Humber S. A., Jain S., Williams W. P., III, Zhao S., Bentley G. E., Tsutsui K., Kriegsfeld L. J. Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge. Endocrinology. 149 (10): 4958—4969. 2008.

Poling M. C., Kim J., Dhamija S., Kauffman A. S. Development, sex steroid regulation, and phenotypic characterization of RFamide-related peptide (Rfrp) gene expression and RFamide receptors in the mouse hypothalamus. Endocrinology. 153 (4): 1827—1840. 2012.

Kirby E. D., Geraghty A. C., Ubuka T., Bentley G. E., Kaufer D. Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats. Proc. Natl. Acad. Sci. USA. 106 (27): 11 324—11 329. 2009.

Gingerich S., Wang X., Lee P., Dhillon S., Chalmers J., Koletar M., Belsham D. D. The generation of an array of clonal, immortalized cell models from the rat hypothalamus: analysis of melatonin effects on kisspeptin and gonadotropin-inhibitory hormone neurons. Neuroscience. 162 (4): 1134—1140. 2009.

Son Y. L., Ubuka T., Narihiro M., Fukuda Y., Hasunuma I., Yamamoto K., Belsham D. D., Tsutsui K. Molecular basis for the activation of gonadotropin-inhibitory hormone gene transcription by corticosterone. Endocrinology. 155 (5): 1817—1826. 2014.

Soga T., Dalpatadu S. L., Wong D. W., Parhar I. S. Neonatal dexamethasone exposure down-regulates GnRH expression through the GnIH pathway in female mice. Neuroscience. 218: 56—64. 2012.

Choi Y. J., Habibi H. R., Kil G. S., Jung M. M., Choi C. Y. Effect of cortisol on gonadotropin inhibitory hormone (GnIH) in the cinnamon clownfish, Amphiprion melanopus. Biochem. Biophys. Res. Commun. 485 (2): 342—348. 2017.

Peragine D. E., Pokarowski M., Mendoza-Viveros L., Swift-Gallant A., Cheng H. M., Bentley G. E., Holmes M. M. RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal. Proc. Natl. Acad. Sci. USA. 114 (5): 1207—1212. 2017.

Iwasa T., Matsuzaki T., Tungalagsuvd A., Munkhzaya M., Kawami T., Niki H., Kato T., Kuwahara A., Uemura H., Yasui T., Irahara M. Hypothalamic Kiss1 and RFRP gene expressions are changed by a high dose of lipopolysaccharide in female rats. Horm. Behav. 66 (2): 309—316. 2014.

Johnson M. A., Tsutsui K., Fraley G. S. Rat RFamide-related peptide—3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat. Horm. Behav. 51 (1): 171—180. 2007.

Parhar I., Ogawa S., Ubuka T. Reproductive neuroendocrine pathways of social behavior. Front. Endocrinol. 7: 28. 2016.

Geraghty A. C., Muroy S. E., Zhao S., Bentley G. E., Kriegsfeld L. J., Kaufer D. Knockdown of hypothalamic RFRP3 prevents chronic stress-induced infertility and embryo resorption. Elife. 4 : e04316. 2015.

Bernard D. J., Tran S. Mechanisms of activin-stimulated FSH synthesis: the story of a pig and a FOX. Biol. Reprod. 88 (3): 78. 2013.

Matzuk M. M., Kumar T. R., Shou W., Coerver K. A., Lau A. L., Behringer R. R., Finegold M. J. Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development. Recent Prog. Horm. Res. 51: 123—154. 1996.

Hashimoto O., Tsuchida K., Ushiro Y., Hosoi Y., Hoshi N., Sugino H., Hasegawa Y. cDNA cloning and expression of human activin bE subunit. Mol. Cell. Endocrinol. 194 (1—2): 117—122. 2002.

Gold E., Jetly N., O'Bryan M. K., Meachem S., Srinivasan D., Behuria S., Sanche-Partida L. G., Woodruff T., Hedwards S., Wang H., McDougall H., Casey V., Niranjan B., Patella S., Risbridger G. Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo. Am. J. Pathol. 174 (1): 184—195. 2009.

Fortin J., Ongaro L., Li Y., Tran S., Lamba P., Wang Y., Zhou X., Bernard D. J. Minireview: Activin signaling in gonadotropes: What does the FOX say... to the SMAD? Mol. Endocrinol. 29 (7): 963—977. 2015.

Fernandez-Vazquez G., Kaiser U. B., Albarracin C. T., Chin W .W. Transcriptional activation of the gonadotropin-releasing hormone receptor gene by activin A. Mol. Endocrinol. 10 (4): 356—366. 1996.

DePaolo L. V., Mercado M., Guo Y., Ling N. Increased follistatin (activin-binding protein) gene expression in rat anterior pituitary tissue after ovariectomy may be mediated by pituitary activin. Endocrinology. 132 (5): 2221—2228. 1993.

Thompson T. B., Woodruff T. K., Jardetzky T. S. Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-b ligand:receptor interactions. EMBO J. 22 (7): 1555—1566. 2003.

Sandoval-Guzman T., Gongrich C., Moliner A., Guo T., Wu H., Broberger C., Ibanez C. F. Neuroendocrine control of female reproductive function by the activin receptor ALK7. FASEB J. 26 (12): 4966—4976. 2012.

Jin J. M., Yang W. X. Molecular regulation of hypothalamus-pituitary-gonads axis in males. Gene. 551 (1): 15—25. 2014.

McNeilly A. S., Crawford J. L., Taragnat C., Nicol L., McNeilly J. R. The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reprod. Suppl. 61: 463—476. 2003.

del Re E., Sidis Y., Fabrizio D. A., Lin H. Y., Schneyer A. Reconstitution and analysis of soluble inhibin and activin receptor complexes in a cell-free system. J. Biol. Chem. 279 (51): 53 126—53 135. 2004.

Kupershmidt L., Amit T., Bar-Am O., Youdim M. B., Blumenfeld Z. The neuroprotective effect of activin A and B: implication for neurodegenerative diseases. J. Neurochem. 103 (3): 962—971. 2007.

Tsuchida K., Nakatani M., Yamakawa N., Hashimoto O., Hasegawa Y., Sugino H. Activin isoforms signal through type I receptor serine/threonine kinase ALK7. Mol. Cell. Endocrinol. 220 (1—2): 59—65. 2004.

Makanji Y., Zhu J., Mishra R., Holmquist C., Wong W. P., Schwartz N. B., Mayo K. E., Woodruff T. K. Inhibin at 90: from discovery to clinical application, a historical review. Endocr. Rev. 35 (5): 747—794. 2014.

Robertson D. M., Stephenson T., Pruysers E., McCloud P., Tsigos A., Groome N., Mamers P., Burger H. G. Characterization of inhibin forms and their measurement by an inhibin a-subunit ELISA in serum from postmenopausal women with ovarian cancer. J. Clin. Endocrinol. Metab. 87 (2): 816—824. 2002.

Antenos M., Stemler M., Boime I., Woodruff T. K. N-linked oligosaccharides direct the differential assembly and secretion of inhibin a- and bA-subunit dimmers. Mol. Endocrinol. 21 (7): 1670—1684. 2007.

Walton K. L., Makanji Y., Wilce M. C., Chan K. L., Robertson D. M., Harrison C. A. A common biosynthetic pathway governs the dimerization and secretion of inhibin and related transforming growth factor b (TGFb) ligands. J. Biol. Chem. 284 (14): 9311—9320. 2009.

Zhu J., Lin S. J., Zou C., Makanji Y., Jardetzky T. S., Woodruff T. K. Inhibin a-subunit N terminus interacts with activin type IB receptor to disrupt activin signaling. J. Biol. Chem. 287 (11): 8060—8070. 2012.

Lewis K. A., Gray P. C., Blount A. L., MacConell L. A., Wiater E., Bilezikjian L. M., Vale W. Betaglycan binds inhibin and can mediate functional antagonism of activin signaling. Nature. 404 (6776): 411—414. 2000.

Lerch T. F., Shimasaki S., Woodruff T. K., Jardetzky T. S. Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions. J. Biol. Chem. 282 (21): 15 930—15 939. 2007.

Schneyer A. L., Wang Q., Sidis Y., Sluss P. M. Differential distribution of follistatin isoforms: application of a new FS315-specific immunoassay. J. Clin. Endocrinol. Metab. 89 (10): 5067—5075. 2004.

Harrington A. E., Morris-Triggs S. A., Ruotolo B. T., Robinson C. V., Ohnuma S., Hyvonen M. Structural basis for the inhibition of activin signalling by follistatin. EMBO J. 25 (5): 1035—1045. 2006.

Kaiser U. B., Lee B. L., Carroll R. S., Unabia G., Chin W. W., Childs G. V. Follistatin gene expression in the pituitary: localization in gonadotropes and folliculostellate cells in diestrous rats. Endocrinology. 130 (5): 3048—3056. 1992.

Kimura F., Bonomi L.M., Schneyer A. L. Follistatin regulates germ cell nest breakdown and primordial follicle formation. Endocrinology. 152 (2): 697—706. 2011.

Jorgez C. J., Klysik M., Jamin S. P., Behringer R. R., Matzuk M. M. Granulosa cell-specific inactivation of follistatin causes female fertility defects. Mol. Endocrinol. 18 (4): 953—967. 2004.

Schneyer A., Schoen A., Quigg A., Sidis Y. Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG). Endocrinology. 144 (5): 1671—1674. 2003.

Tortoriello D. V., Sidis Y., Holtzman D. A., Holmes W. E., Schneyer A. L. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 142 (8): 3426—3434. 2001.

Sidis Y., Schneyer A. L., Keutmann H. T. Heparin and activin-binding determinants in follistatin and FSTL3. Endocrinology. 146 (1): 130—136. 2005.

Xia Y., Sidis Y., Schneyer A. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Mol. Endocrinol. 18 (4): 979—994. 2004.

Mukherjee A., Sidis Y., Mahan A., Raher M. J., Xia Y., Rosen E. D., Bloch K. D., Thomas M. K., Schneyer A. L. FSTL3 deletion reveals roles for TGF-b family ligands in glucose and fat homeostasis in adults. Proc. Natl. Acad. Sci. USA. 104 (4): 1348—1353. 2007.

Roa J., Tena-Sempere M. Connecting metabolism and reproduction: roles of centre energy sensors and key molecular mediators. Mol. Cell Endocrinol. 397 (1—2): 4—14. 2014.

Roumaud P., Martin L. Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity. Horm. Mol. Biol. Clin. Invest. 24 (1): 25—45. 2015.

Mounzih K., Lu R., Chehab F. F. Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology. 138 (3): 1190—1193. 1997.

Pinto-Fochi M. E., Pytlowanciv E. Z., Reame V., Rafacho A., Ribeiro D. L., Taboga S. R., Goes R. M. A high-fat diet fed during different periods of life impairs steroidogenesis of rat Leydig cells. Reproduction. 152 (6): 795—808. 2016.

Dupont J., Pollet-Villard X., Reverchon M., Mellouk N, Levy R. Adipokines in human reproduction. Horm. Mol. Biol. Clin. Investig. 24 (1): 11—24. 2015.

Mathew H., Castracane V. D., Mantzoros C. Adipose tissue and reproductive health. Metabolism. 7: pii: S0026-0495(17)30309-8. 2017.

Garcia-Galiano D., Allen S. J., Elias C. F. Role of the adipocyte-derived hormone leptin in reproductive control. Horm. Mol. Biol. Clin. Investig. 19 (3): 141—149. 2014.

Balasko M., Soos S., Szekely M., Petervari E. Leptin and aging: Review and questions with particular emphasis on its role in the central regulation of energy balance. J. Chem. Neuroanat. 61—62: 248—255. 2014.

Park H., Ahima R. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism. 64 (1): 24—34. 2015.

Munzberg H., Morrison C. Structure, production and signaling of leptin. Metabolism. 64 (1): 13—23. 2015.

Sainz N., Barrenetxe J., Moreno-Aliaga M., Martinez J. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 64 (1): 35—46. 2015.

Patterson С., Villanueva E., Greenwald-Yarnell M., Rajala M., Gonzalez I. E., Saini N., Jones J., Myers M. G., jr. Leptin action via LepR-b Tyr1077 contributes to the control of energy balance and female reproduction. Mol. Metab. 1 (1—2): 61—69. 2012.

Roa J. Role of GnRH neurons and their neuronal afferents as key integrators between food intake regulatory signals and the control of reproduction. Int. J. Endocrinol. 2013: 518 046. 2013.

Ahima R. S., Dushay J., Flier S. N., Prabakaran D., Flier J. S. Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99 (3): 391—395. 1997.

Roman E. A., Ricci A. G., Faletti A. G. Leptin enhances ovulation and attenuates the effects produced by food restriction. Mol. Cell Endocrinol. 242 (1—2): 33—41. 2005.

Teerds K. J., de Rooij D. G., Keijer J. Functional relationship between obesity and male reproduction: from humans to animal models. Hum. Reprod. Update. 17 (5): 667—683. 2011.

Caprio M., Fabbrini E., Isidori A., Aversa A., Fabbri A. Leptin in reproduction. Trends Endocrinol. Metab. 12 (2): 65—72. 2001.

Landry D., Cloutier F., Martin L. Implications of leptin in neuroendocrine regulation of male reproduction. Reprod. Biol. 13 (1): 1—14. 2013.

Farooqi I. S. Leptin and the onset of puberty: insights from rodent and human genetics. Sem. Reprod. Med. 20 (2): 139—144. 2002.

Tena-Sempere M., Barreiro M. Leptin in male reproduction: the testis paradigm. Mol. Cell Endocrinol. 188 (1—2): 9—13. 2002.

Hausman G., Barb C., Lents C. Leptin and reproductive function. Biochimie. 94 (10): 2075—2081. 2012.

Ha S., Baver S., Huo L., Gata A., Hairston J., Huntoon N., Li W., Zhang T., Benecchi E. J., Ericsson M., Hentges S. T., Btшrbжk C. Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PLoS One. 8 (10): e77622. 2013.

Quennell J., Mulligan A., Tups A., Liu X., Phipps S., Kemp C., Herbison A. Grattan D., Anderson G. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Neuroendocrinology. 150 6): 2805—2812. 2009.

Roa J., Herbison A. E. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 153 (11): 5587—5599. 2012.

Manfredi-Lozano M., Roa J., Ruiz-Pino F., Piet R., Garcia-Galiano D., Pineda R., Zamora A., Leon S., Sanchez-Garrido M. A., Romero-Ruitz A., Dieguez C., Vazquez M. J., Herbison A. E., Pinilla L., Tena-Sempere M. Defining a novel leptin — melanocortin — kisspeptin pathway involved in the metabolic control of puberty. Mol. Metab. 5 (10): 844—857. 2016.

Egan O. K., Inglis M. A., Anderson G. M. Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice. J. Neurosci. 37 (14): 3875—3886. 2017.

Ratra D. V., Elias C. F. Chemical identity of hypothalamic neurons engaged by leptin in reproductive control. J. Chem. Neuroanat. 61—62: 233—238. 2014.

Gamba M., Pralong F. P. Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin. Mol. Cell Endocrinol. 254—255: 133—139. 2006.

Gonzales C., Voirol M. J., Giacomini M., Gaillard R. C., Pedrazzini T., Pralong F. P. The neuropeptide Y Y1 receptor mediates NPY-induced inhibition of the gonadotrope axis under poor metabolic conditions. FASEB J. 18 (1): 137—129. 2004.

Crown A., Clifton D. C., Steiner R. A. Neuropeptide signaling in the integration of metabolism andreproduction. Neuroendocrinology. 86 (3): 175—182. 2007.

Muroi Y., Ishii T. A novel neuropeptide Y neuronal pathway linking energy state and reproductive behavior. Neuropeptides. 59: 1—8. 2016.

Toufexis D. J., Kyriazis D., Woodside B. Chronic neuropeptide Y Y5 receptor stimulation suppresses reproduction in virgin female and lactating rats. J. Neuroendocrinol. 14 (6): 492—497. 2002.

Шпаков А. О. Сигнальные системы мозга, регулируемые инсулином, ИФР-1 и лептином, в условиях преддиабета и сахарного диабета 2-го типа. Цитология. 56 (11): 789— 799. 2014. [Shpakov A. O. The role of alterations in the brain signaling systems regulated by insulin, IGF-1 and leptin in the transition of impaired glucose tolerance to overt type 2 diabetes mellitus. Tsitologiia. 56 (11): 789—799. 2014. (In Russ.)].

Shpakov A. O., Derkach K. V., Berstein L. M. Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases. Future Science OA (FSO). 1 (3): FSO25. doi: 10.4155/fso.15.23. 2015.

Шпаков А. О. Функциональное состояние гипоталамо-гипофизарно-гонадной системы при сахарном диабете. Пробл. эндокринологии. 56 (5): 23—29. [Shpakov A. O. The functional state of the hypothalamic-pituitary-gonadal system in diabetes mellitus. Problemy Endokrinologii. 56 (5): 23—29. 2010. (In Russ.)].

McDuffie I. A., Akhter N., Childs G. W. Regulation of leptin mRNA and protein expression in pituitary somatotropes. J. Histochem. Cytochem. 52 (2): 263—273. 2004.

Yu W. H., Kimura M., Walczewska A., Karanth S., McCann S. M. Role of leptin in hypothalamic-pituitary function. Proc. Natl. Acad. Sci. USA. 94 (3): 1023—1028. 1997.

Akhter Т., Crane C., Childs G. Pituitary leptin — a paracrine regulator of gonadotropes: a review. Open Neuroendocrinol. J. 4: 25—42. 2011.

Caminos J.E., Nogueiras R., Gaytбn F., Pineda R., Gonzбlez C. R., Barreiro M. L., Castaсo J. P., Malagуn M. M., Pinilla L., Toppari J., Diйguez C., Tena-Sempere M. Novel expression and direct effects of adiponectin in the rat testis. Endocrinology. 149 (7): 3390—3402. 2008.

Rak A., Mellouk N., Froment P., Dupont J. Adiponectin and resistin: Potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species. Reproduction. 153 (6): R215—R226. 2017.

Kadowaki T., Yamauchi T. Adiponectin and adiponectin receptors. Endocr. Rev. 26 (3): 439—451. 2005.

Liu Z., Xiao T., Peng X., Li G., Hu F. APPLs: More than just adiponectin receptor binding proteins. Cell. Signal. 32: 76—84. 2017.

Wang C., Xin X., Xiang R., Ramos F. J., Liu M., Lee H. J., Chen H., Mao X., Kikani C. K., Liu F., Dong L. Q. Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. J. Biol. Chem. 284 (46): 31 608—31 615. 2009.

Combs T. P., Marliss E. B. Adiponectin signaling in the liver. Rev. Endocr. Metab. Disord. 15 (2): 137—147. 2014.

Kos K., Harte A. L., da Silva N. F., Tonchev A., Chaldakov G., James S., Snead D. R., Hoggart B., O'Hare J. P., McTernan P. G., Kumar S. Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J. Clin. Endocrinol. Metab. 92 (3): 1129—1136. 2007.

Kubota N., Yano W., Kubota T., Yamauchi T., Itoh S., Kumagai H., Kozono H., Takamoto I., Okamoto S., Shiuchi T., Suzuki R., Satoh H., Tsuchida A., Moroi M., Sugi K., Noda T., Ebinuma H., Ueta Y., Kondo T., Araki E., Ezaki O., Nagai R., Tobe K., Terauchi Y., Ueki K., Monokoshi Y., Kadowaki T. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell. Metab. 6 (1): 55—68. 2007.

Kusminski C. M., McTernan P. G., Schraw T., Kos K., O'Hare J. P., Ahima R., Kumar S., Scherer P. E. Adiponectin complexes in human cerebrospinal fluid: Distinct complex distribution from serum. Diabetologia. 50 (3): 634—642. 2007.

Cheng X. B., Wen J. P., Yang J., Yang Y., Ning G., Li X. Y. GnRH secretion is inhibited by adiponectin through activation of AMP-activated protein kinase and extracellular signal-regulated kinase. Endocrine. 39 (1): 6—12. 2011.

Wen J. P., Lv W. S., Yang J., Nie A. F., Cheng X. B., Yang Y., Ge Y., Li X. Y., Ning G. Globular adiponectin inhibits GnRH secretion from GT1—7 hypothalamic GnRH neurons by induction of hyperpolarization of membrane potential. Biochem. Biophys. Res. Commun. 371 (4): 756—761. 2008.

Wen J. P., Liu C., Bi W. K., Hu Y. T., Chen Q., Huang H., Liang J. X., Li L. T., Lin L. X., Chen G. Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons. J. Endocrinol. 214 (2): 177—189. 2012.

Kiezun M., Smolinska N., Maleszka A., Dobrzyn K., Szeszko K., Kaminski T. Adiponectin expression in the porcine pituitary during the estrous cycle and its effect on LH and FSH secretion. Am. J. Physiol. Endocrinol. Metab. 307 (11): 1038—1046. 2014.

Lu M., Tang Q., Olefsky J. M., Mellon P. L., Webster N. J. Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbT2 gonadotropes. Mol. Endocrinol. 22 (3): 760—771. 2008.

Psilopanagioti A., Papadaki H., Kranioti E. F., Alexandrides T. K., Varakis J. N. Expression of adiponectin and adiponectin receptors in human pituitary gland and brain. Neuroendocrinology. 89 (1): 38—47. 2009.

Rodriguez-Pacheco F., Martinez-Fuentes A. J., Tovar S., Pinilla L., Tena-Sempere M., Dieguez C., Castano J. P., Malagon M. M. Regulation of pituitary cell function by adiponectin. Endocrinology. 148 (1): 401—410. 2007.

Reverchon M., Maillard V., Froment P., Rame C., Dupont J. Adiponectin and resistin: a role in the reproductive functions? M*ed. Sci. 29 (4): 417—424. 2013.