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.
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