Attenuation of palmitic acid-induced lysyl oxidase overexpression in ovary may improveme ovulation in obesity by metformin: Study
Obesity is a pandemic issue. Compelling evidence indicates that obesity is also inextricably linked with infertility, particularly in women. Infertility in obese women is largely attributed to menstrual irregularities, poor gamete development, impaired uterine receptivity, and ovulation disorders. The deleterious effects of ovulation disorders, either irregular ovulation or anovulation, are particularly worthy of attention since ovulation disorders not only are a common cause of female infertility but also may impact women’s health in the long term via alteration of the endocrine milieu, leading to increased risks of endometrial and breast cancers. Therefore, elucidating the mechanism underlying ovulation disorders in obese individuals is of paramount importance for ensuring the well-being of women. Accumulated evidence indicates that hormonal disturbance, insulin resistance, and inflammation may all play a role in the development of ovulation disorders in individuals with obesity. Increased palmitic acid (PA) in individuals with obesity can cause LOX upregulation via the activation of hypoxia-inducible factor-1a (HIF-1a), resulting in abnormal collagen deposition in the ovary and anovulation, which can be ameliorated by metformin therapy. The underlying cause of anovulation in individuals with obesity is poorly defined, and accumulating evidence indicates that hormonal disturbance, insulin resistance, and inflammation may all play a role in the development of ovulation disorders in individuals with obesity. However, it remains to be determined whether PA plays a role in the regulation of LOX expression, thus disrupting ovarian extracellular matrix (ECM) remodelling in the ovary and resulting in impaired ovulation in individuals with obesity.
Metformin is commonly prescribed to treat anovulation associated with insulin resistance in infertile women. Observational studies indicate that metformin can lower serum androgen levels and restore menstrual cyclicity.
Zhang et al. postulated that metformin might correct PA-induced abnormal ovarian ECM remodelling through downregulation of LOX expression, thereby improving ovulation in individuals with obesity. Herein, authors addressed these hypotheses by using human ovarian tissue and granulosa cells obtained from women with obesity as well as from an obese rat model. PA concentration and LOX protein abundance and activity in follicular fluid and ovarian tissue were compared between control (n ¼ 21) subjects, patients with obesity with ovulation (n ¼ 22), and patients with obesity with anovulation (n ¼ 16). The effect of PA on LOX protein expression, and the underlying mechanism, was examined in primary human granulosa cells in vitro. The improvements in obesity conditions induced by LOX inhibition combined with metformin were investigated in a high-fat diet-induced obese rat model.
The abundance of PA concentration and LOX activity was measured via a LOX activity assay and ELISA, respectively. The effect of PA on LOX protein expression was examined in the presence or absence of inhibitors of signalling molecules and siRNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were subsequently conducted to further identify the responsible transcription factor. The role of metformin in the treatment of anovulation by LOX inhibition was investigated in a high-fat diet (HFD)-induced obese rat model. The numbers of retrieved total oocytes and metaphase II oocytes were recorded upon ovarian stimulation. Masson’s trichrome staining was used to measure the total collagen content, and immunohistochemical staining and western blotting were used to measure LOX, HIF-1a, and collagen I and IV in the ovary.
Significantly increased FFA, LOX, and collagen abundance were observed in the ovaries of obese women with anovulation, compared to healthy controls or obese women with ovulation. In a HFD-induced obese rat model, metformin corrected the distortion of ovarian morphology by decreasing LOX and collagen protein abundance in the ovary and improving oestrous cyclicity and ovulation. PA increased LOX expression via the activation of HIF-1a in human granulosa cells, which was attenuated by metformin.
This study demonstrated that PA in obesity induces LOX expression and excessive collagen deposition in the ovary, which may restrict follicle growth, impair ovulation, and lead to infertility. Metformin improved ovulatory function in individuals with obesity by attenuating LOX expression and excessive collagen deposition in the ovary. This is the first study showing that metformin may be of therapeutic value for improving ovulation in individuals with obesity through its local effect on ECM remodelling in the ovary. Since study’s in vitro study of human granulosa cells showed that metformin could attenuate PA-induced LOX expression via attenuation of HIF-1a activation, authors believe that the effects of metformin observed in this study are independent of its systemic effect on insulin sensitivity and chronic inflammation.
Study findings provide new insight into the mechanism of anovulation in obesity. Results have shown that increased PA levels in individuals with obesity are a cause of LOX overexpression in the ovary, which can result in excessive collagen deposition, thus leading to impaired ovulation. Moreover, authors found that these effects of PA could be ameliorated by metformin, which further justifies the therapeutic use of metformin in the treatment of ovulation disorders in individuals with obesity.
Source: Zhang et al.; Human Reproduction Open, 2024, 2024(1),
hoae002 https://doi.org/10.1093/hropen/hoae002
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