{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:41:23Z","timestamp":1784025683741,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Male infertility is a common disease affecting male reproductive health. Leptin is an important hormone that regulates various physiological processes, including reproductive function. However, few experimental studies have been carried out to elucidate the mechanism of leptin's effects on male reproductive function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The purpose of this study was to investigate the effects of leptin on testicular spermatogenesis and its mechanism, so as to provide potential targets for the treatment of patients with spermatogenic dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Testicular tissues were collected from eight prostate cancer patients undergoing surgical castration. GPR125\u2010positive spermatogonia were isolated by two consecutive magnetic activated cell sorting (MACS), followed by incubation with conditioned medium. To identify the signaling pathway(s) involved in the effects of leptin, undifferentiated spermatogonia were treated with different concentrations of leptin and antagonists of leptin\u2010related pathways. The proliferative effect of leptin was evaluated by cell counting using a hemocytometer. Expressions of p\u2010AKT, p\u2010ERK, p\u2010STAT, and p\u2010S6K were determined by western blotting analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Leptin promoted the growth of human GPR125\u2010positive spermatogonia in a concentration\u2010dependent manner. The most significant proliferative effect was observed using 100\u00a0ng\/mL leptin after 6 days of culture. Leptin significantly increased the phosphorylation of STAT3, AKT, and ERK in undifferentiated spermatogonia. Phosphatidylinositol 3\u2010kinase (PI3K) inhibitor LY294002 inhibited the leptin\u2010induced activation of AKT, ERK, and downstream S6K. Treatment with the mammalian target of rapamycin (mTOR) inhibitor rapamycin also inhibited S6K phosphorylation. Moreover, both LY294002 and rapamycin were found to inhibit the leptin\u2010induced proliferation of undifferentiated spermatogonia. These results suggested that the leptin\u2010induced proliferation of GPR125\u2010positive spermatogonia was dependent on the PI3K\/AKT\/mTOR pathway. Further exploration of proliferation and apoptotic markers suggested that leptin may alleviate cell apoptosis by regulating the expression of Bax and FasL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A certain concentration of leptin (25\u223c100\u00a0ng\/mL) could promote proliferation of undifferentiated spermatogonia, which was mediated by PI3K\/AKT\/mTOR pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.13811","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T05:35:17Z","timestamp":1705469717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Leptin promotes proliferation of human undifferentiated spermatogonia by activating the PI3K\/AKT\/mTOR pathway"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5899-6707","authenticated-orcid":false,"given":"Song","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Urology Gongli Hospital of Shanghai Pudong New Area  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xiaoxuan","sequence":"additional","affiliation":[{"name":"School of Medicine Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Yixuan","sequence":"additional","affiliation":[{"name":"School of Medicine Qingdao University  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai","family":"Zhikang","sequence":"additional","affiliation":[{"name":"Department of Urology Gongli Hospital of Shanghai Pudong New Area  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-021-09687-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27123"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.13541"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.02.053"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.585887"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioac109"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.13982"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121749"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62848"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.71038"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1392"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/19396368.2022.2113930"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2021.10.006"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000508105"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.02.005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.12.008"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094713"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOU.0000000000000762"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2018.10.006"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2014.00198"},{"issue":"5","key":"e_1_2_8_22_1","first-page":"7065","article-title":"Role of leptin and the leptin receptor in the pathogenesis of varicocele\u2010induced testicular dysfunction","volume":"17","author":"Zhang J","year":"2018","journal-title":"Mol Med Rep"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20191593"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1146849"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-23-0111"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204971"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323347"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.118028"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.10.004"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.02.017"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.07.017"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.043"},{"issue":"3","key":"e_1_2_8_33_1","first-page":"281","article-title":"Spermatogonial stem cell renewal in the mouse. 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