АДИПОНЕКТИН, КАК ЭНДОГЕННЫЙ РЕГУЛЯТОР ГИПОТАЛАМО-ГИПОФИЗАРНО-ГОНАДНОЙ ОСИ

Адипонектин — важнейший адипокин, контролирующий пищевое поведение и энергетический гомеостаз. В настоящее время получено много данных в пользу того, что адипонектин также регулирует функции репродуктивной системы, причем его мишенями являются гипоталамические нейроны, ответственные за синтез и секрецию гонадолиберина, гонадотрофы гипофиза, продуцирующие лютеинизирующий гормон, и гонады. В тканях-мишенях, являющихся звеньями гипоталамо-гипофизарно-гонадной оси, обнаружены все основные компоненты сигнальной системы, регулируемой адипонектином, включая сам адипонектин и оба типа адипонектиновых рецепторов. Нарушения в адипонектиновых сигнальных путях приводят к развитию репродуктивных дисфункций, вследствие чего эти пути в будущем могут стать одной из важнейших мишеней для терапии заболеваний мужской и женской репродуктивных систем. В обзоре рассмотрено современное состояние проблемы участия адипонектина в функционировании гипоталамо-гипофизарно-гонадной оси и взаимосвязи между функциональным статусом репродуктивной системы и активностью адипонектиновой системы в гипоталамических нейронах, гонадотрофах и гонадах.

1. Khalil RB, El Hachem C. Adiponectin in eating disorders. Eat Weight Disord. 2014;19(1):3-10.

2. Balsan GA, Vieira JL, Oliveira AM et al. Relationship between adiponectin, obesity and insulin resistance. Rev Assoc Med Bras (1992). 2015;61(1):72-80.

3. Rak A, Mellouk N, Froment P et al. Adiponectin and resistin: Potential metabolic signals affecting hypothalamopituitary gonadal axis in females and males of different species. Reproduction. 2017;153(6):R215-R226.

4. Richards AA, Stephens T, Charlton HK et al. Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: evidence for regulation of multimerization by alterations in posttranslational modifications. Mol Endocrinol. 2006;20(7):1673-1687.

5. Martin LJ. Implications of adiponectin in linking metabolism to testicular function. Endocrine. 2014;46(1):16-28.

6. Yamauchi T, Iwabu M, Okada-Iwabu M et al. Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab. 2014;28(1):15-23.

7. Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016;23(5):770-784.

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

9. Pajvani UB, Hawkins M, Combs TP et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279(13):12152-12162.

10. Peake PW, Kriketos AD, Campbell LV et al. The metabolism of isoforms of human adiponectin: studies in human subjects and in experimental animals. Eur J Endocrinol. 2005;153(3):409-417.

11. Andersen KK, Frystyk J, Wolthers OD et al. Gender differences of oligomers and total adiponectin during puberty: a cross-sectional study of 859 Danish school children. J Clin Endocrinol Metab. 2007;92(5):1857-1862.

12. Böttner A, Kratzsch J, Müller G et al. Gender differences of adiponectin levels develop during the progression of puberty and are related to serum androgen levels. J Clin Endocrinol Metab. 2004;89(8):4053-4061.

13. Martos-Moreno GA, Barrios V, Argente J. Normative data for adiponectin, resistin, interleukin 6, and leptin/receptor ratio in a healthy Spanish pediatric population: Relationship with sex steroids. Eur J Endocrinol. 2006;155(3):429-434.

14. Wilkinson M, Brown R, Imran SA et al. Adipokine gene expression in brain and pituitary gland. Neuroendocrinology. 2007;86(3):191-209.

15. Caminos JE, Nogueiras R, Gaytán F et al. Novel expression and direct effects of adiponectin in the rat testis. Endocrinology. 2008;149(7):3390-3402.

16. Yamauchi T, Kamon J, Ito Y et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762-769.

17. Yamauchi T, Nio Y, Maki T et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13(3):332-339.

18. Pal China S, Sanyal S, Chattopadhyay N. Adiponectin signaling and its role in bone metabolism. Cytokine. 2018. pii: S1043-4666(18)30260-6.

19. Heiker JT, Wottawah CM, Juhl C et al. Protein kinase CK2 interacts with adiponectin receptor 1 and participates in adiponectin signaling. Cell Signal. 2009;21(6):936-942.

20. Wang C, Xin X, Xiang R et al. Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. J Biol Chem. 2009;284(46):31608-31615.

21. Buechler C, Wanninger J, Neumeier M. Adiponectin receptor binding proteins — recent advances in elucidating adiponectin signalling pathways. FEBS Lett. 2010;584(20):4280-4286.

22. Liu Z, Xiao T, Peng X et al. APPLs: More than just adiponectin receptor binding proteins. Cell Signal. 2017;32:76-84.

23. Xu Y, Wang N, Ling F et al. Receptor for activated C-kinase 1, a novel binding partner of adiponectin receptor 1. Biochem Biophys Res Commun. 2009;378(1):95-98.

24. Charlton HK, Webster J, Kruger S et al. ERp46 binds to AdipoR1, but not AdipoR2, and modulates adiponectin signalling. Biochem Biophys Res Commun. 2010;392(2):234-239.

25. Lampropoulou E, Lymperopoulou A, Charonis A. Reduced expression of ERp46 under diabetic conditions in β-cells and the effect of liraglutide. Metabolism. 2016;65(1):7-15.

26. Combs TP, Marliss EB. Adiponectin signaling in the liver. Rev Endocr Metab Disord. 2014;15(2):137-147.

27. Deepa SS, Zhou L, Ryu J et al. APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCζ signaling pathway. Mol Endocrinol. 2011;25(10):1773-1785.

28. Ceddia RB, Somwar R, Maida A et al. Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia. 2005;48(1):132-139.

29. Wang C, Mao X, Wang L et al. Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem. 2007;282(11):7991-7996.

30. Miller RA, Chu Q, Le Lay J et al. Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J Clin Invest. 2011;121(6):2518-2528.

31. Xin X, Zhou L, Reyes CM et al. APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab. 2011;300(1):E103-E110.

32. Yan J, Gan L, Qi R et al. Adiponectin decreases lipids deposition by p38 MAPK/ATF2 signaling pathway in muscle of broilers. Mol Biol Rep. 2013;40(12):7017-7025.

33. Yamauchi T, Kadowaki T. Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab. 2013;17(2):185-196.

34. Holland WL, Miller RA, Wang ZV et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011;17(1):55-63.

35. Almabouada F, Diaz-Ruiz A, Rabanal-Ruiz Y et al. Adiponectin receptors form homomers and heteromers exhibiting distinct ligand binding and intracellular signaling properties. J Biol Chem. 2013;288(5):3112-3125.

36. Kosel D, Heiker JT, Juhl C et al. Dimerization of adiponectin receptor 1 is inhibited by adiponectin. J Cell Sci. 2010;123(Pt 8):1320-1328.

37. Berner HS, Lyngstadaas SP, Spahr A et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone. 2004;35(4):842-849.

38. Liu BH, Wang PH, Wang YC et al. Fasting regulates the expression of adiponectin receptors in young growing pigs. J Anim Sci. 2008;86(12):3377-3384.

39. Bullen JW Jr, Bluher S, Kelesidis T et al. Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice. Am J Physiol Endocrinol Metab. 2007;292(4):E1079-E1086.

40. Bonnard C, Durand A, Vidal H et al. Changes in adiponectin, its receptors and AMPK activity in tissues of diet-induced diabetic mice. Diabetes Metab. 2008;34(1):52-61.

41. Liu BH, Wang YC, Wu SC et al. Insulin regulates the expression of adiponectin and adiponectin receptors in porcine adipocytes. Domest Anim Endocrinol. 2008;34(4):352-359.

42. Zeng Q, Isobe K, Fu L et al. Effects of exercise on adiponectin and adiponectin receptor levels in rats. Life Sci. 2007;80(5):454-459.

43. Christiansen T, Paulsen SK, Bruun JM et al. Diet-induced weight loss and exercise alone and in combination enhance the expression of adiponectin receptors in adipose tissue and skeletal muscle, but only diet-induced weight loss enhanced circulating adiponectin. J Clin Endocrinol Metab. 2010;95(2):911-919.

44. Kusminski CM, McTernan PG, Schraw T et al. Adiponectin complexes in human cerebrospinal fluid: Distinct complex distribution from serum. Diabetologia. 2007;50(3):634-642.

45. Kubota N, Yano W, Kubota T et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6(1):55-68.

46. Kos K, Harte AL, da Silva NF et al. Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. J Clin Endocrinol Metab. 2007;92(3):1129-1136.

47. Cheng XB, Wen JP, Yang J et al. GnRH secretion is inhibited by adiponectin through activation of AMP-activated protein kinase and extracellular signal-regulated kinase. Endocrine. 2011;39(1):6-12.

48. Neumeier M, Weigert J, Buettner R et al. Detection of adiponectin in cerebrospinal fluid in humans. Am J Physiol Endocrinol Metab. 2007;293(4):E965-E969.

49. Reverchon M, Maillard V, Froment P et al. Adiponectin and resistin: a role in the reproductive functions? Med Sci (Paris). 2013;29(4):417-424.

50. Wen JP, Lv WS, Yang J et al. Globular adiponectin inhibits GnRH secretion from GT1-7 hypothalamic GnRH neurons by induction of hyperpolarization of membrane potential. Biochem Biophys Res Commun. 2008;371(4):756-761.

51. Wen JP, Liu C, Bi WK et al. Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons. J Endocrinol. 2012;214(2):177-189.

52. Chu S, Ferro TJ. Sp1: Regulation of gene expression by phosphorylation. Gene. 2005;348:1-11.

53. Lu M, Tang Q, Olefsky JM et al. Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LβT2 gonadotropes. Mol Endocrinol. 2008;22(3):760-771.

54. Psilopanagioti A, Papadaki H, Kranioti EF et al. Expression of adiponectin and adiponectin receptors in human pituitary gland and brain. Neuroendocrinology. 2009;89(1):38-47.

55. Kiezun M, Smolinska N, Maleszka A et al. Adiponectin expression in the porcine pituitary during the estrous cycle and its effect on LH and FSH secretion. Am J Physiol Endocrinol Metab. 2014; 307(11): 1038-1046.

56. Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S et al. Regulation of pituitary cell function by adiponectin. Endocrinology. 2007; 148(1): 401-410.

57. Thomas S, Kratzsch D, Schaab M et al. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil Steril. 2013;99(5):1256-1263.

58. Heinz JF, Singh SP, Janowitz U et al. Characterization of adiponectin concentrations and molecular weight forms in serum, seminal plasma, and ovarian follicular fluid from cattle. Theriogenology. 2015;83(3):326-333.

59. Bai J, Liu Y, Niu GF et al. Relationship between adiponectin and testosterone in patients with type 2 diabetes. Biochem Med (Zagreb). 2011;21(1):65-70.

60. Pfaehler A, Nanjappa MK, Coleman ES et al. Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis. Toxicol Lett. 2012;209(1):78-85.

61. Kadivar A, Heidari Khoei H, Hassanpour H et al. Correlation of adiponectin mRNA abundance and its receptors with quantitative parameters of sperm motility in rams. Int J Fertil Steril. 2016;10(1):127-135.

62. Bjursell M, Ahnmark A, Bohlooly-Y M et al. Opposing effects of adiponectin receptors 1 and 2 on energy metabolism. Diabetes. 2007;56(3):583–593.

63. Landry D, Paré A, Jean S et al. Adiponectin influences progesterone production from MA-10 Leydig cells in a dose-dependent manner. Endocrine. 2015;48(3):957-967.

64. Chabrolle C, Tosca L, Dupont J. Regulation of adiponectin and its receptors in rat ovary by human chorionic gonadotrophin treatment and potential involvement of adiponectin in granulosa cell steroidogenesis. Reproduction. 2007;133(4):719-731.

65. Maillard V, Uzbekova S, Guignot F et al. Effect of adiponectin on bovine granulosa cell steroidogenesis, oocyte maturation and embryo development. Reprod Biol Endocrinol. 2010;8:23.

66. Tabandeh MR, Hosseini A, Saeb M et al. Changes in the gene expression of adiponectin and adiponectin receptors (AdipoR1 and AdipoR2) in ovarian follicular cells of dairy cow at different stages of development. Theriogenology. 2010;73(5):659-669.

67. Chabrolle C, Tosca L, Ramé C et al. Adiponectin increases insulin-like growth factor I-induced progesterone and estradiol secretion in human granulosa cells. Fertil Steril. 2009;92(6):1988-1996.

68. Gutman G, Barak V, Maslovitz S et al. Recombinant luteinizing hormone induces increased production of ovarian follicular adiponectin in vivo: Implications for enhanced insulin sensitivity. Fertil Steril. 2009;91(5):1837-1841.

69. Ledoux S, Campos DB, Lopes FL et al. Adiponectin induces periovulatory changes in ovarian follicular cells. Endocrinology. 2006;147(11):5178-5186.

70. Ortega HH, Rey F, Velazquez MM et al. Developmental programming: Effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep. Biol Reprod. 2010;82(6):1065-1075.

71. Lagaly DV, Aad PY, Grado-Ahuir JA et al. Role of adiponectin in regulating ovarian theca and granulosa cell function. Mol Cell Endocrinol. 2008;284(1-2):38-45.

72. Robinson RS, Woad KJ, Hammond AJ et al. Angiogenesis and vascular function in the ovary. Reproduction. 2009;138(6):869-881.

73. Chu MC, Cosper P, Orio F et al. Insulin resistance in postmenopausal women with metabolic syndrome and the measurements of adiponectin, leptin, resistin, and ghrelin. Am J Obstet Gynecol. 2006;194(1):100-104.

74. Im JA, Lee JW, Lee HR et al. Plasma adiponectin levels in postmenopausal women with or without long-term hormone therapy. Maturitas. 2006;54(1):65-71.

75. Chalvatzas N, Dafopoulos K, Kosmas G et al. Effect of ovarian hormones on serum adiponectin and resistin concentrations. Fertil Steril. 2009;91(4):1189-1194.

76. Sumino H, Takahashi T, Itoh T et al. Plasma adiponectin levels in post-menopausal women receiving hormone replacement therapy. J Int Med Res. 2004;32(6):639-645.

77. Rouen PA, Lukacs JL, Reame NE. Adipokine concentrations in nonobese women: A study of reproductive aging, body mass index, and menstrual cycle effects. Biol Res Nurs. 2010;12(1):54-61.

78. Merki-Feld GS, Imthurn B, Rosselli M et al. Serum concentrations of high-molecular weight adiponectin and their association with sex steroids in premenopausal women. Metabolism. 2011;60(2):180-185.

79. Leung KC, Xu A, Craig ME et al. Adiponectin isoform distribution in women–relationship to female sex steroids and insulin sensitivity. Metabolism. 2009;58(2):239-245.