BMAL1 Dysregulation as a Contributing Mechanism Linking Obesity to Oocyte and Endometrial Dysfunction in IVF.

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-translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine-methionine 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-where oocyte quality is controlled for-show reduced implantation rates in several but not all cohorts-a 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.