Low-dose spironolactone ameliorates adipose tissue inflammation and apoptosis in letrozole-induced PCOS rat model.

BACKGROUND OF STUDY: Globally, many reproductive aged women are affected by polycystic ovarian syndrome (PCOS), which is a common endocrine and metabolic disorder that is linked with adipose dysfunction and chronic low-grade inflammation. Spironolactone (SPL), a mineralocorticoid receptor blocker has been documented as a metabolic modulator. However, its immunomodulatory effect in PCOS is unknown. Therefore, the present study hypothesized that SPL would ameliorate adipose dysfunction and inflammation in experimental PCOS animals. MATERIALS AND METHODS: Female Wistar rats that were 8 weeks old were allocated into three groups. Group 1 received vehicle (distilled water; p.o.), group 2 received letrozole (1 mg/kg; p.o.) and group 3 received letrozole plus SPL (0.25 mg/kg, p.o.). The administration was performed once daily for 21 days. RESULTS: The experimental PCOS animals showed insulin resistance, hyperinsulinemia and hyperandrogenism as well as oxidative stress and elevated inflammatory biomarkers (NF-kB/TNF-/IL-6) as well as a significant decrease in triglycerides, total cholesterol, free fatty acids, GSH and G6PD in the adipose tissue of PCOS animals. In addition, immunohistochemical assessment of adipose tissue showed significant expression of BAX and inflammasome, indicating apoptosis and inflammation compared to control animals. Nevertheless, administration of SPL attenuated these perturbations. CONCLUSION: Altogether, the present study suggests that low-dose spironolactone confers protection against adipose dysfunction in experimental PCOS animals by attenuating inflammation, oxidative stress and cellular apoptosis.

Acetate restores hypothalamic-adipose kisspeptin status in a rat model of PCOS by suppression of NLRP3 immunoreactivity.

PURPOSE: Polycystic ovary syndrome (PCOS) is a complex reproductive event that is delineated by endocrine/metabolic disorders. Alteration of kisspeptin status in the hypothalamus and adipose tissue is critical to increased endocrine/metabolic derangements in PCOS individuals, aggravating the clinical manifestation of PCOS and its complications. Short chain fatty acids (SCFAs) are crucial modulators of metabolic homeostasis. However, the role of SCFAs, particularly acetate on hypothalamic-adipose kisspeptin status (HAKS) in PCOS model is unknown. The present study hypothesized acetate as a key player in restoration of deranged HAKS, associated with experimental PCOS model. METHODS: Three groups (n = 6/group) of female Wistar rats (120-150 g) were used. The groups were treated (po) for 21 days with vehicle, letrozole (1 mg/kg) with/without acetate (200 mg/kg) respectively. RESULTS: Letrozole-treated animals had impaired glucose homeostasis, elevated testosterone, leptin and LH/FSH ratio and decreased GnRH and adiponectin with ovarian tissues revealing degenerated follicles and disrupted morphology. These animals also showed increased concentration of hypothalamic triglyceride (TG)/total cholesterol (TC), free fatty acid (FFA), and decreased concentration of TG/TC/FFA in visceral adipose tissue (VAT) with an increase in hypothalamic and VAT malondialdehyde, NF-κB/TNF-α and decreased glutathione/G6PD and hypothalamic but not VAT kisspeptin. Immunohistochemical analysis revealed the expression of NLRP3 inflammasome in the hypothalamus and VAT and all these changes were attenuated by acetate. CONCLUSIONS: Altogether, the present results demonstrate that PCOS is characterized with hypothalamic-adipose inflammation, associated with immunohistochemical expression of NLRP3 with significant alteration of hypothalamic but not adipose kisspeptin. The results suggest that acetate restores kisspeptin status in PCOS animals. This beneficial effect is accompanied by repressed NLRP3 immunoreactivity.