Butyrate alleviates adipose mitochondrial dysfunction and inflammation in experimental model of polycystic ovarian syndrome by modulating SIRT1-dependent mechanism

Purpose Impaired adipose tissue (AT) remodeling has been suggested as a pathophysiological driver of endocrinometabolic events in polycystic ovarian syndrome (PCOS) models. Mitochondrial dysfunction, especially in the adipocyte plays a key role in AT inflammation that possibly aggravates endocrine/metabolic phenotypes in PCOS. Studies have reported short-chain fatty acids (SCFAs) as metabolic modulators that potentiate energy homeostasis. Butyrate, a unique form of SCFAs improves metabolic function by inhibition of histone deacetylase activity. The present study therefore hypothesized that butyrate would reverse adipose mitochondrial dysfunction/inflammation and endocrine/metabolic features of PCOS in experimental rats. Methods Eight-week-old nulliparous Wistar rats were assigned into groups ( n = 5): control (CTL), butyrate (BUT), letrozole (LEZ), and LEZ + BUT. Induction of PCOS was by letrozole (1 mg/kg) for 21 days. After the confirmation of PCOS, rats were treated with butyrate (200 mg/kg) for 6 weeks. Results Animals with PCOS expressed multiple ovarian cysts and hormonal/metabolic changes characterized by hyperandrogenism/hypoestrogenism, elevated anti-Mullerian hormone and hyperinsulinemia/insulin resistance. In addition, animals also demonstrated increased plasma triglyceride, decreased adiponectin, increased leptin with corresponding decrease in adipose triglyceride, and increased inflammatory markers (NF-kB, TNF-α). A significant increase in adipose caspase-6, lipid peroxidation, and decreased GSH and mitochondrial mitofusin 2/ATP synthase were also observed in experimental PCOS rats. These alterations were accompanied by increased levels of adipose MIF. Nevertheless, the administration of butyrate alleviated these alterations in the adipose and ovarian tissues of PCOS animals. Conclusion The results suggest the ameliorative effect of butyrate on adipose mitochondrial dysfunction and/or inflammation in PCOS by modulating SIRT1-dependent pathway.