Adiponectin orchestrates testosterone suppression in biological pathways

Abstract

This current review highlights adiponectin engagement with AdipoRl and AdipoR2 which subsequently triggers pathways such as AMPK, PPARα, and MAPK, thereby modulating testicular steroidogenesis. Adiponectin's actions on Leydig and adrenal cells inhibit androgen secretion by suppressing the steroidogenic acute regulatory protein (StAR). Given that StAR facilitates cholesterol to testosterone conversion, AMPK inhibits this process by modulating cholesterol transport and suppressing StAR expression through multiple avenues. Furthermore, adiponectin-induced PPARα activation impedes mitochondrial cholesterol influx, further modulating androgen biosynthesis. The suppressive influence of PPARα on steroidogenic genes, notably StAR, is evident. Collectively, adiponectin signalling predominantly attenuates androgen production, ensuring metabolic and reproductive equilibrium. Imbalances, as seen in conditions like hypogonadism and obesity-related infertility, highlight their crucial roles and potential clinical interventions for reproductive disorders.

Keywords

Adiponectin / Testosterone / Steroidogenic acute regulatory protein / Steroidogenesis / Leydig cells

Conflict of interest statement

Authors declare no conflicts of interest in this study.

Funding

The study received no extramural funding.

Authors’ contributions

Ekhoye Ehitare Ikekhuamen and Imonna Kingsley conducted the research. They jointly authored the manuscript, carried out the literature review, made revisions, and gave final approval for the manuscript. Ekhoye Ehitare Ikekhuamen was responsible for the study's conceptualization and design.

Publisher’s Note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] Han Y, Sun Q, Chen W, Gao Y, Ye J, Chen Y, et al. New advances of adiponectin in regulating obesity and related metabolic syndromes. J Pharm Anal 2023. doi: 10.1016/j.jpha.2023.12.003.

[2] Cândido APC, Geloneze B, Calixto A, Vasques ACJ, Freitas RN, Freitas SN, et al. Adiponectin, HOMA-adiponectin, HOMA-IR in children and adolescents: Ouro Preto study. Indian J Pediatr 2021; 88(4): 336-344.

[3] Zhang YQ, Fan S, Wang WQ, Lau WB, Dai JL, Zhang HF, et al. Hyperlipidemic plasma molecules bind and inhibit adiponectin activity. J Diabetes Investig 2022; 13(6): 947-954.

[4] Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci 2017; 18(6). doi: 10.3390/ijms18061321.

[5] Choi HM, Doss HM, Kim KS. Multifaceted physiological roles of adiponectin in inflammation and diseases. Int J Mol Sci 2020; 21(4). doi: 10.3390/ijms21041219.

[6] Kim JY, Barua S, Jeong YJ, Lee JE. Adiponectin: The potential regulator and therapeutic target of obesity and Alzheimer’s disease. Int J Mol Sci 2020; 21(17). doi:10.3390/ijms2n76419.

[7] Hussain MK, Deli FA, Algenabi AHA, Abdul-Rudha KH. Adiponectin gene polymorphisms as a predictor for development of type 2 diabetes mellitus in Iraqi population. Gene 2018; 662: 118-122.

[8] Choubey M, Ranjan A, Bora PS, Baltazar F, Krishna A. Direct actions of adiponectin on changes in reproductive, metabolic, and anti-oxidative enzymes status in the testis of adult mice. Gen Comp Endocrinol 2019; 279: 1-11.

[9] Kawwass JF, Summer R, Kallen CB. Direct effects of leptin and adiponectin on peripheral reproductive tissues: A critical review. Mol Hum Reprod 2015; 21(8): 617-632.

[10] Thomas S, Kratzsch D, Schaab M, Scholz M, Grunewald S, Thiery J, et al. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil Steril 2013; 99(5): 1256-1263.e3.

[11] Elfassy Y, Bastard JP, McAvoy C, Fellahi S, Dupont J, Levy R. Adipokines in semen: Physiopathology and effects on spermatozoas. Int J Endocrinol 2018; 2018: 3906490.

[12] da Silva Rosa SC, Liu M, Sweeney G. Adiponectin synthesis, secretion and extravasation from circulation to interstitial space. Physiology (Bethesda) 2021; 36(3): 134-149.

[13] Xu A, Chan KW, Hoo RLC, Wang Y, Tan KCB, Zhang J, et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem 2005; 280(18): 18073-18080.

[14] Lee MJ, Fried SK. Sex-dependent depot differences in adipose tissue development and function; Role of sex steroids. J Obes Metab Syndr 2017; 26(3): 172-180.

[15] Dudek P, Kozakowski J, Zgliczyński W. The effects of testosterone replacement therapy in men with age-dependent hypogonadism on body composition, and serum levels of leptin, adiponectin, and C-reactive protein. Endokrynol Pol 2020; 71(5): 382-387.

[16] Pfaehler A, Nanjappa MK, Coleman ES, Mansour M, Wanders D, Plaisance EP, et al. Regulation of adiponectin secretion by soy isoflavones has implication for endocrine function of the testis. Toxicol Lett 2012; 209(1): 78-85.

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

[18] Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, et al. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: A potential mechanism of insulin sensitization. Endocrinology 2002; 143(3): 998-1007.

[19] Fisman EZ, Tenenbaum A. Adiponectin: A manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol 2014; 13(1): 103.

[20] Patil S, Veerabhadra Goud GK, Shivashankar RN, Anusuya SK, Ganesh V. Association of adiponectin levels with polycystic ovary syndrome among Indian women. Bioinformation 2022; 18(10): 864-869.

[21] Gao S, Su S, Zhang E, Zhang Y, Liu J, Xie S, et al. The effect of circulating adiponectin levels on incident gestational diabetes mellitus: Systematic review and meta-analysis. Ann Med 2023; 55(1): 2224046.

[22] Adu-Gyamfi EA, Fondjo LA, Owiredu WKBA, Czika A, Nelson W, Lamptey J, et al. The role of adiponectin in placentation and preeclampsia. Cell Biochem Funct 2020; 38(1): 106-117.

[23] Wen L, Fu H, Saffery R, Tong C, Liu Y, Kilby MD, et al. Cord blood adiponectin and leptin concentrations in monochorionic twins with selective intrauterine growth restriction and their associations with childhood growth trajectories. Pediatr Obes 2023; 18(7): e13034.

[24] Ouh YT, Cho HW, Lee JK, Choi SH, Choi HJ, Hong JH. CXC chemokine ligand 1 mediates adiponectin-induced angiogenesis in ovarian cancer. Tumour Biol J Int Soc Oncodevelopmental Biol Med 2019; 42(4): 1010428319842699.

[25] Słabuszewska-Jóźwiak A, Lukaszuk A, Janicka-Kośnik M, Wdowiak A, Jakiel G. Role of leptin and adiponectin in endometrial cancer. Int J Mol Sci 2022; 23(10). doi: 10.3390/ijms23105307.

[26] Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond) 2008; 32 (Suppl 7): S13-S18.

[27] Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin receptors: A review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab 2014; 28(1): 15-23.

[28] Pascolutti R, Erlandson SC, Burri DJ, Zheng S, Kruse AC. Mapping and engineering the interaction between adiponectin and T-cadherin. J Biol Chem 2020; 295(9): 2749-2759.

[29] Ruan H, Dong LQ. Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 2016; 8(2): 101-109.

[30] Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, et al. APPLI binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol 2006; 8(5): 516-523.

[31] Wang C, Xin X, Xiang R, Ramos FJ, Liu M, Lee HJ, et al. Yin-Yang regulation of adiponectin signaling by APPL isoforms in muscle cells. J Biol Chem 2009; 284(46): 31608-31615.

[32] Shklyaev SS, Melnichenko GA, Volevodz NN, Falaleeva NA, Ivanov SA, Kaprin AD, et al. Adiponectin: A pleiotropic hormone with multifaceted roles. Probi Endokrinol (Mosk) 2021; 67(6): 98-112.

[33] Li C, Cao Y, Ren Y, Zhao Y, Wu X, Si S, et al. The adiponectin receptor agonist, AdipoRon, promotes reproductive hormone secretion and gonadal development via the hypothalamic-pituitary-gonadal axis in chickens. Poult Sci 2023; 102(2): 102319.

[34] Feyzi M, Tabandeh MR, Shariati M, Edalatmanesh MA. Age associated changes in transcription of adiponectin, AdipoRi and AdipoR2 genes in pancreas of rats. Cell J 2020; 22(Suppl 1): 61-67.

[35] Mahabady MK, Shamsi MM, Ranjbar R, Tabandeh MR, Khazaeel K. Quercetin improved histological structure and upregulated adiponectin and adiponectin receptors in the placenta of rats with gestational diabetes mellitus. Placenta 2021; 106: 49-57.

[36] Mirza SS, Shafique K, Shaikh AR, Khan NA, Anwar Qureshi M. Association between circulating adiponectin levels and polycystic ovarian syndrome. J Ovarian Res 2014; 7: 18.

[37] Iglesias MJ, Eiras S, Piñeiro R, López-Otero D, Gallego R, Fernández ÁL, et al. Gender differences in adiponectin and leptin expression in epicardial and subcutaneous adipose tissue. Findings in patients undergoing cardiac surgery. Rev Española Cardiol (English Ed 2006; 59(12): 1252-1260.

[38] Yarrow JF, Beggs LA, Conover CF, McCoy SC, Beck DT, Borst SE. Influence of androgens on circulating adiponectin in male and female rodents. PLoS One 2012; 7(10): e47315.

[39] Kadivar A, Heidari Khoei H, Hassanpour H, Golestanfar A, Ghanaei H. 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.

[40] Duliban M, Gorowska-Wojtowicz E, Tworzydlo W, Rak A, Brzoskwinia M, Krakowska I, et al. Interstitial leydig cell tumorigenesis-leptin and adiponectin signaling in relation to aromatase expression in the human testis. Int J Mol Sci 2020; 21(10). doi: 10.3390/ijms2n03649.

[41] Thomas S, Kratzsch D, Schaab M, Scholz M, Grunewald S, Thiery J, et al. Seminal plasma adipokine levels are correlated with functional characteristics of spermatozoa. Fertil Steril 2013; 99(5): 1256-1263.e3.

[42] Ocón-Grove OM, Krzysik-Walker SM, Maddineni SR, Hendricks GL, Ramachandran R. Adiponectin and its receptors are expressed in the chicken testis: Influence of sexual maturation on testicular ADIPOR1 and ADIPOR2 mRNA abundance. Reproduction 2008; 136(5): 627-638.

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

[44] Rossi GP, Sticchi D, Giuliani L, Bernante P, Zavattiero S, Pessina AC, et al. Adiponectin receptor expression in the human adrenal cortex and aldosterone-producing adenomas. Int J Mol Med 2006; 17(6): 975-980.

[45] Li P, Sun F, Cao HM, Ma QY, Pan CM, Ma JH, et al. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: Adiponectin regulates steroidogenesis. Biochem Biophys Res Commun 2009; 390(4): 1208-1213.

[46] Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X, Fang Q, et al. Adiponectin activates AMP-activated protein kinase in muscle cells via APPL1/LKB1- dependent and phospholipase C/Ca²⁺/Ca²⁺/calmodulin-dependent protein kinase kinase-dependent pathways. J Biol Chem 2009; 284(33): 22426-22435.

[47] de Oliveira M, Rodrigues BM, Olimpio RMC, Mathias LS, De Sibio MT, Moretto FCF, et al. Adiponectin and serine/threonine kinase Akt modulation by triiodothyronine and/or LY294002 in 3T3-L1 adipocytes. Lipids 2019; 54(2-3): 133-140.

[48] Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, et al. Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: Comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 2005; 54(12): 3358-3370.

[49] Xin X, Zhou L, Reyes CM, Liu F, Dong LQ. APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1- MKK3-p38 MAPK pathway. Am J Physiol Endocrinol Metab 2011; 300(1): E103-10.

[50] Liu S, Liu H, Liu Y, Zhang J, Liu Z, Zheng Z, et al. Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells. Cell Prolif 2023; 56(3): e13370.

[51] Ramanjaneya M, Conner AC, Brown JEP, Chen J, Digby JE, Barber TM, et al. Adiponectin (15-36) stimulates steroidogenic acute regulatory (StAR) protein expression and cortisol production in human adrenocortical cells: Role of AMPK and MAPK kinase pathways. Biochim Biophys Acta 2011; 1813(5): 802-809.

[52] Miller WL, Bose HS. Early steps in steroidogenesis: Intracellular cholesterol trafficking. J Lipid Res 2011; 52(12): 2111-2135.

[53] Abdou HS, Bergeron F, Tremblay JJ. A cell-autonomous molecular cascade initiated by AMP-activated protein kinase represses steroidogenesis. Mol Cell Biol 2014; 34(23): 4257-4271.

[54] Li M, Xue K, Ling J, Diao FY, Cui YG, Liu JY. The orphan nuclear receptor NR4A1 regulates transcription of key steroidogenic enzymes in ovarian theca cells. Mol Cell Endocrinol 2010; 319(1-2): 39-46.

[55] Shea-Eaton W, Sandhoff TW, Lopez D, Hales DB, McLean MP. Transcriptional repression of the rat steroidogenic acute regulatory (StAR) protein gene by the AP-1 family member c-Fos. Mol Cell Endocrinol 2002; 188(1-2): 161-170.

[56] Sirianni R, Nogueira E, Bassett MH, Carr BR, Suzuki T, Pezzi V, et al. The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1. J Cell Sci 2010; 123(Pt 22):3956-3965.

[57] Fleury A, Mathieu AP, Ducharme L, Hales DB, LeHoux JG. Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR). J Steroid Biochem Mol Biol 2004; 91(4-5): 259-271.

[58] Massip-Salcedo M, Zaouali MA, Padrissa-Altés S, Casillas-Ramirez A, Rodés J, Roselló-Catafau J, et al. Activation of peroxisome proliferator- activated receptor-alpha inhibits the injurious effects of adiponectin in rat steatotic liver undergoing ischemia-reperfusion. Hepatology 2008; 47(2): 461-472.

[59] Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, et al. Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. Toxicology 2008; 250(2-3): 75-81.

[60] Schultz R, Yan W, Toppari J, Völkl A, Gustafsson JA, Pelto-Huikko M. Expression of peroxisome proliferator-activated receptor alpha messenger ribonucleic acid and protein in human and rat testis. Endocrinology 1999; 140(7): 2968-2975.

[61] Plummer SM, Dan D, Quinney J, Hallmark N, Phillips RD, Millar M, et al. Identification of transcription factors and coactivators affected by dibutylphthalate interactions in fetal rat testes. Toxicol Sci 2013; 132(2): 443-457.

[62] Sugawara T, Holt JA, Kiriakidou M, Strauss JF. Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR) gene. Biochemistry 1996; 35(28): 9052-9059.

[63] Toda K, Okada T, Miyaura C, Saibara T. Fenofibrate, a ligand for PPARa, inhibits aromatase cytochrome P450 expression in the ovary of mouse. J Lipid Res 2003; 44(2): 265-270.

[64] Kortam MA, Alawady AS, Hamid Sadik NA, Fathy N. Fenofibrate mitigates testosterone induced benign prostatic hyperplasia via regulation of Akt/FOXO3a pathway and modulation of apoptosis and proliferation in rats. Arch Biochem Biophys 2022; 723: 109237.

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

[66] Tsujimura A, Takada S, Matsuoka Y, Nakayama J, Takao T, Miyagawa Y, et al. Adiponectin and testosterone in patients with symptoms of late- onset hypogonadism: Is there a link? Int J Urol 2009; 16(10): 830-835.

[67] Shigehara K, Kato Y, Konaka H, Kawaguchi S, Nohara T, Izumi K, et al. The correlation between erectile function and adiponectin levels in men with late-onset hypogonadism. Aging Male 2022; 25(1): 249-254.

[68] Roumaud P, Martin LJ. 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 Investig 2015; 24(1): 25-45.