The role of omentin-1 in female reproduction: a critical review

Communication between tissues and the coordination of body functions are regulated by the endocrine and nervous systems. Endocrine glands secrete hormones – chemical messengers distributed throughout the body via the bloodstream [ 1 ]. These hormones act on nearly all tissues, underscoring their fundamental role in maintaining homeostasis. A central hormonal network regulating reproduction is the hypothalamic–pituitary–gonadal axis, which governs the physiology of both female and male reproductive systems. The hypothalamus and pituitary gland serve as key endocrine regulators, while the ovary functions as an active endocrine unit. By synthesizing steroid hormones from cholesterol through the activity of multiple enzymes, the ovary controls female sexual development and reproductive behavior [ 1 ]. Female fertility also depends on energy metabolism, tightly coordinated with reproductive demands [ 2 ]. In this context, reproductive studies increasingly aim to identify molecular markers capable of optimizing gamete quality and improving reproductive efficiency during disrupted energy metabolism. Importantly, white adipose tissue is now recognized as an endocrine organ that produces biologically active molecules termed adipokines, which directly regulate systemic physiology and integrate energy balance with reproductive capacity [ 3 ]. In this review, we highlight omentin-1, an adipokine of emerging significance; we summarize current knowledge on its expression and function in the reproductive system within hypothalamus–pituitary– ovary (HPO) axis, as well as its involvement in endocrine-related disorders. Given its pleiotropic actions, omentin-1 may represent a promising molecular target for future therapeutic strategies in reproductive pathologies linked to disrupted energy balance.

In recent years, an increasing number of scientific studies have demonstrated that omentin-1 is a significant player in various reproductive disorders and pathologies ( Fig. 4 Fig. 4. The role of omentin-1 in selected reproductive disorders. PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin. Created in BioRender. ). One such reproductive pathology is polycystic ovary syndrome (PCOS) leading to infertility by inhibiting ovulation, which affects up to 12% of women of reproductive age worldwide, and its prevalence is increasing [ 115 ]. Studies have shown that omentin-1 plasma levels are reduced in patients with PCOS, both in obese and non-obese individuals suffering from that pathology [ 116 ]. Another study demonstrated that plasma omentin-1 levels are positively correlated with sex hormone-binding globulin (SHBG) levels in women with PCOS [ 117 ], suggesting that higher omentin-1 concentrations may support SHBG production independently of other conditions. Since SHBG affects the binding and availability of sex hormones and its low levels are characteristic of metabolic and hormonal changes in PCOS, the presence of higher omentin-1 levels may contribute to mitigating hormonal dysfunction. Moreover, omentin-1 levels in the FF of women with PCOS are significantly correlated with elevated levels of androgens synthesized by theca cells, such as 17OH-pregnenolone, dehydroepiandrosterone, and T [ 118 ], indicating that higher omentin concentrations in the follicular environment are associated with the overproduction of androgens typical for PCOS. Since these androgens are strongly linked to the main clinical features of PCOS, the association with omentin suggests that this adipokine plays a role in modulating ovarian hormonal activity. The role of omentin-1 in selected reproductive disorders. PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin. Created in BioRender. Another important reproductive disorder affecting many women is endometriosis, which is characterized by the presence of tissue similar to the endometrial lining outside the uterus. This condition is associated with inflammation and other health complications, such as the formation of cysts [ 118 , 119 ]. It was shown that omentin-1 concentrations were the highest in peripheral blood (around 498.6 ng/ml) and significantly lower in peritoneal fluid (around 230.9 ng/ml) and endometriotic cyst fluid (around 228 ng/ml) in women with endometriosis [ 120 ]. This indicates that omentin-1 is primarily a circulating adipokine, with limited local production or accumulation within endometrial tissues. Therefore, omentin-1 does not appear to be largely involved in the local inflammatory processes associated with endometriosis [ 121 ]. It can thus be concluded that omentin-1 acts rather as a systemic regulator with protective properties, while its reduced presence within endometriotic lesions and peritoneal fluid may promote a local predominance of pro-inflammatory adipokines, supporting the development and persistence of endometriotic centers. Another study showed no differences in serum omentin-1 concentrations between women with endometriosis and the healthy group. Moreover, omentin-1 levels did not correlate with the inflammatory marker C-reactive protein [ 122 ]. The absence of differences suggests that omentin-1 does not play a significant role in the pathogenesis of endometriosis or that its effects are secondary and systemic rather than local or inflammatory, which is consistent with the conclusions of the study by Wójtowicz et al . [ 123 ]. Another reproduction-related disorder, very frequently observed among women, is ovarian cancer, with over 300 000 new cases a year [ 122 ]. Studies have shown that mesothelial cells of patients with advanced ovarian cancer exhibit significantly lower omentin-1 expression compared to healthy tissue, and circulating omentin-1 levels are reduced compared to healthy women [ 123 ]. This reduction results from the action of pro-inflammatory cytokines, such as TNF-α, in the tumor microenvironment, which locally suppresses omentin-1 expression [ 123 ]. As shown this adipokine limits cancer cell proliferation by increasing insulin-dependent glucose uptake in adipocytes, thereby reducing the local energy availability for tumor cells [ 123 ]. Interestingly, in an in vivo model of mouse, administration of omentin-1 led to slower tumor growth and inhibition of glycolysis in ovarian cancer cells [ 123 ]. Therefore, the low levels of omentin-1 in the ovarian cancer microenvironment act as a barrier that limits cell invasion and growth, helping disease progression. As follows, omentin-1 may serve both as a prognostic marker and a potential therapeutic agent in ovarian cancer. Omentin-1 also has high diagnostic value in detecting endometrial cancer, with the area under the curve value (AUC) of 0.86, making it one of the most effective adipokines analyzed in this context by Cymbaluk-Płoska et al . [ 124 ]. Furthermore, lower omentin-1 concentrations were observed in cases of lymphatic vessel invasion, lymph node metastases and deep endometrial infiltration, suggesting that a decrease in this adipokine level is associated with more advanced stage of that cancer [ 124 ]. Omentin-1 may therefore serve as a useful diagnostic biomarker in endometrial cancer, and its serum concentration could help in assessing disease stage and metastasis risk, which makes it a potential tool for patient monitoring and therapy planning. Omentin is also an important protein in pathologies observed during pregnancy. A study using a mouse model of preeclampsia characterized by increased blood pressure in mothers demonstrated that administration of recombinant omentin-1 resulted in a significant reduction in maternal blood pressure, increased fetal and placental weight, and improved fetal-to-placenta weight ratio [ 125 ]. Omentin-1 administration enhanced endothelial function in aortic rings, reduced placental necrosis, increased the number of CD31-positive vessels in the labyrinth zone of the placenta, and decreased local concentrations of pro-inflammatory factors in aortic and placental murine tissues [ 125 ]. These findings suggest the therapeutic potential of omentin-1 in treating endothelial dysfunction associated with preeclampsia. Moreover, in women with gestational diabetes mellitus (GDM), serum omentin-1 levels are significantly lower compared to healthy women, measuring 338.7 ± 49.26 in healthy women and 289.2 ± 20.22 in women with GDM [ 126 ]. Lower omentin-1 concentrations were associated with an increased risk of developing GDM, suggesting that omentin-1 plays a role in glucose regulation during pregnancy. Combined with other inflammatory and metabolic markers (hs-CRP, homocysteine, fibrinogen), omentin-1 levels contributed to the development of a highly sensitive and specific predictive model for GDM risk [ 126 ]. Thus, omentin-1 may be applied as a biomarker in pregnant women for the early identification of patients at risk of GDM, making it possible to implement earlier clinical intervention if needed. In conclusion, omentin-1 is increasingly recognized as a crucial metabolic-reproductive mediator acting along the HPO axis. Its presence and hormonal regulation within hypothalamic neurons, pituitary cells, and ovarian cells indicate that this adipokine integrates peripheral energy status with central and gonadal endocrine activity. Through activation of key intracellular pathways, including AMPK, PI3K/AKT, ERK1/2, and PKA, omentin-1 modulates gonadotropin release, Gc proliferation, and steroid hormone synthesis, thereby influencing reproductive competence. The breed- and tissue-specific effects observed in animal models underscore its context-dependent roles and suggest complex feedback mechanisms between metabolic and reproductive systems. Future research should aim to identify the specific omentin-1 receptor, clarify its crosstalk with reproductive hormones, and explore its therapeutic potential as a target for metabolic-reproductive disorders impairing fertility.

The authors declare that this study was conducted in the absence of commercial or financial relationships that could be construed as potential conflicts of interest.