{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:59:26Z","timestamp":1781780366682,"version":"3.54.5"},"reference-count":28,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD094380"],"award-info":[{"award-number":["R01HD094380"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Uterine leiomyomas are the most common benign tumors of the female reproductive system. Obese individuals have a higher burden of uterine leiomyoma, yet the mechanism relating obesity and leiomyoma development remains unknown. In this study, we observe the effect of adipocyte coculture and leptin treatment on human myometrium and leiomyoma cells. We isolated primary leiomyoma and myometrium cells from hysterectomy or myomectomy patients. Protein expression levels of phosphorylated ERK1\/2\/total ERK1\/2, phosphorylated STAT3\/total STAT3, and phosphorylated AKT1\/2\/3\/total AKT1\/2\/3 were quantified using immunoblotting in immortalized and primary leiomyoma and myometrial cells cocultured with human adipocytes and treated with leptin. An enzyme-linked immunosorbent assay (ELISA) was used to assess pro-inflammatory, fibrotic, and angiogenic factors in immortalized human myometrium and leiomyoma cells treated with leptin. The effects of STAT3, ERK, and AKT inhibitors were assessed in leiomyoma cell lines additionally cultured with adipocytes. Adipocyte coculture and leptin treatment increases the expression of JAK2\/STAT3, MAPK\/ERK, and PI3K\/AKT signaling while inhibitors suppressed this effect. Leptin induces a tumor-friendly microenvironment through upregulation of pro-inflammatory (IFN\u03b3, IL-8, IL-6, GM-CSF, MCP-1, and TNF-\u03b1), fibrotic (TGF-\u03b21, TGF-\u03b22, and TGF-\u03b23), and angiogenic (VEGF-A, HGF, and Follistatin) factors in human leiomyoma cells. Furthermore, adipocyte coculture and leptin treatment increases leiomyoma cells growth through activation of MAPK\/ERK, JAK2\/STAT3, and PI3k\/AKT signaling pathways. Finally, STAT3, ERK, and AKT inhibitor treatment suppressed PCNA, TNF-\u03b1, TGF-\u03b23, and VEGF-A intracellular staining intensity in both adipocyte coculture and leptin treated leiomyoma cells. These findings suggest that, in obese women, adipocyte secreted hormone or adipocytes may contribute to leiomyoma development and growth by activating leptin receptor signaling pathways.<\/jats:p>","DOI":"10.3390\/nu15030715","type":"journal-article","created":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T02:04:52Z","timestamp":1675130692000},"page":"715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Adipocyte and Adipokines Promote a Uterine Leiomyoma Friendly Microenvironment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5063-9900","authenticated-orcid":false,"given":"Sadia","family":"Afrin","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malini","family":"Ramaiyer","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umme Aoufa Mafruha","family":"Begum","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Khulna City Medical College Hospital, 25-26, KDA Ave., Khulna 9100, Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa A.","family":"Borahay","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1067\/mob.2003.99","article-title":"High Cumulative Incidence of Uterine Leiomyoma in Black and White Women: Ultrasound Evidence","volume":"188","author":"Baird","year":"2003","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"211.e1","DOI":"10.1016\/j.ajog.2011.12.002","article-title":"The Estimated Annual Cost of Uterine Leiomyomata in the United States","volume":"206","author":"Cardozo","year":"2012","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_3","first-page":"57","article-title":"Adipose Tissue, Obesity and Adipokines: Role in Cancer Promotion. Horm","volume":"21","author":"Booth","year":"2015","journal-title":"Mol. Biol. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1097\/OGX.0000000000000718","article-title":"Cardiometabolic Risk Factors and Benign Gynecologic Disorders","volume":"74","author":"AlAshqar","year":"2019","journal-title":"Obstet. Gynecol. Surv."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"He, Y., Zeng, Q., Li, X., Liu, B., and Wang, P. (2013). The Association between Subclinical Atherosclerosis and Uterine Fibroids. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057089"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"176","DOI":"10.2188\/jea.8.176","article-title":"Body Fat Distribution and Uterine Leiomyomas","volume":"8","author":"Sato","year":"1998","journal-title":"J. Epidemiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1136\/jech-2019-213364","article-title":"Association between Obesity and the Risk of Uterine Fibroids: A Systematic Review and Meta-Analysis","volume":"75","author":"Qin","year":"2021","journal-title":"J. Epidemiol. Community Health"},{"key":"ref_8","unstructured":"(2022, October 03). Peristats|March of Dimes. Available online: https:\/\/www.marchofdimes.org\/peristats\/."},{"key":"ref_9","first-page":"383","article-title":"Leptin Induces Leiomyoma Cell Proliferation and Extracellular Matrix Deposition via JAK2\/STAT3 and MAPK\/ERK Pathways","volume":"3","author":"Reschke","year":"2022","journal-title":"FS Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166564","DOI":"10.1016\/j.bbadis.2022.166564","article-title":"Adipocyte Coculture Induces a Pro-Inflammatory, Fibrotic, Angiogenic, and Proliferative Microenvironment in Uterine Leiomyoma Cells. Biochim. Biophys","volume":"1869","author":"Afrin","year":"2023","journal-title":"Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2020.05.012","article-title":"Simvastatin Ameliorates Altered Mechanotransduction in Uterine Leiomyoma Cells","volume":"223","author":"Afrin","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105856","DOI":"10.1016\/j.phrs.2021.105856","article-title":"Simvastatin Modulates Estrogen Signaling in Uterine Leiomyoma via Regulating Receptor Palmitoylation, Trafficking and Degradation","volume":"172","author":"Afrin","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1097\/01.LAB.0000017499.51216.3E","article-title":"Immortalization of Human Uterine Leiomyoma and Myometrial Cell Lines after Induction of Telomerase Activity: Molecular and Phenotypic Characteristics","volume":"82","author":"Carney","year":"2002","journal-title":"Lab. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1177\/1933719111408111","article-title":"Adipocytes Enhance the Proliferation of Human Leiomyoma Cells Via TNF-\u03b1 Proinflammatory Cytokine","volume":"18","author":"Nair","year":"2011","journal-title":"Reprod. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/S0022-2275(20)42025-5","article-title":"Human Liposarcoma Cell Line, SW872, Secretes Cholesteryl Ester Transfer Protein in Response to Cholesterol","volume":"37","author":"Richardson","year":"1996","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 Years of Image Analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_17","first-page":"242","article-title":"Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy","volume":"21","author":"Borahay","year":"2015","journal-title":"Mol. Med. Camb. Mass"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.coph.2016.11.004","article-title":"Role of Inflammation in Obesity-Related Breast Cancer","volume":"31","author":"Crespi","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1716246","DOI":"10.1155\/2018\/1716246","article-title":"Chronic Inflammation May Enhance Leiomyoma Development by the Involvement of Progenitor Cells","volume":"2018","author":"Orciani","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.7150\/jca.16884","article-title":"Obesity and Cancer: The Role of Adipose Tissue and Adipo-Cytokines-Induced Chronic Inflammation","volume":"7","author":"Divella","year":"2016","journal-title":"J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fonc.2017.00216","article-title":"Obesity and Cancer Metabolism: A Perspective on Interacting Tumor\u2013Intrinsic and Extrinsic Factors","volume":"7","author":"Doerstling","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s13402-019-00428-0","article-title":"Leptin-Induced Signaling Pathways in Cancer Cell Migration and Invasion","volume":"42","author":"Ghasemi","year":"2019","journal-title":"Cell. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.12703\/P6-73","article-title":"Leptin Signaling","volume":"6","author":"Park","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1158\/0008-5472.CAN-06-3075","article-title":"Concomitant Activation of the JAK\/STAT, PI3K\/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells","volume":"67","author":"Saxena","year":"2007","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1042\/BJ20051578","article-title":"Intracellular Signalling Pathways Activated by Leptin","volume":"393","year":"2006","journal-title":"Biochem. J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Haque, I., Ghosh, A., Acup, S., Banerjee, S., Dhar, K., Ray, A., Sarkar, S., Kambhampati, S., and Banerjee, S.K. (2018). Leptin-Induced ER-\u03b1-Positive Breast Cancer Cell Viability and Migration Is Mediated by Suppressing CCN5-Signaling via Activating JAK\/AKT\/STAT-Pathway. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-3993-6"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1093\/humupd\/dmx032","article-title":"Extracellular Matrix in Uterine Leiomyoma Pathogenesis: A Potential Target for Future Therapeutics","volume":"24","author":"Islam","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2058738418779461","DOI":"10.1177\/2058738418779461","article-title":"TNF-\u03b1 Serum Levels Are Elevated in Women with Clinically Symptomatic Uterine Fibroids","volume":"32","author":"Ciebiera","year":"2018","journal-title":"Int. J. Immunopathol. Pharmacol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/3\/715\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:20:39Z","timestamp":1760120439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/3\/715"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,31]]},"references-count":28,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["nu15030715"],"URL":"https:\/\/doi.org\/10.3390\/nu15030715","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,31]]}}}