{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:09:32Z","timestamp":1788887372643,"version":"build-2803163510"},"reference-count":106,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription\u2013translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-\u03b3 signaling and reduced glutamine\u2013methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles\u2014where oocyte quality is controlled for\u2014show reduced implantation rates in several but not all cohorts\u2014a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention.<\/jats:p>","DOI":"10.3390\/ijms27188001","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:46:04Z","timestamp":1788885964000},"page":"8001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BMAL1 Dysregulation as a Contributing Mechanism Linking Obesity to Oocyte and Endometrial Dysfunction in IVF"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-7619","authenticated-orcid":false,"given":"Charalampos","family":"Voros","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Chatzinikolaou","sequence":"additional","affiliation":[{"name":"Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Papadimas","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-5054","authenticated-orcid":false,"given":"Ioannis","family":"Papapanagiotou","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3036-7212","authenticated-orcid":false,"given":"Nektaria","family":"Zagorianakou","sequence":"additional","affiliation":[{"name":"Scientific Laboratory for Innovative Technologies in Internal Medicine, Preventive Medicine and Overall Care, Department of Nursing, School of Health Sciences, University of Ioannina, 45500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9298-2720","authenticated-orcid":false,"given":"Ali Can","family":"Gunes","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Karpouzos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-4305","authenticated-orcid":false,"given":"Kyriakos","family":"Bananis","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospitals NHS Foundation Trust, London SE5 9RS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalampos","family":"Tsimpoukelis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Anastasia","family":"Daskalaki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stylianos","family":"Makrydimas","sequence":"additional","affiliation":[{"name":"Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Pikrides","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Thomakos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-5922","authenticated-orcid":false,"given":"Panagiotis","family":"Antsaklis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-594X","authenticated-orcid":false,"given":"Dimitrios","family":"Loutradis","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-211X","authenticated-orcid":false,"given":"Georgios","family":"Daskalakis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, 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