The effect of magnolol on a polycystic ovary syndrome rat model with insulin resistance

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent reproductive and metabolic disorder. Insulin resistance (IR) is highly associated with and aggravates the symptoms of PCOS. The Insulin sensitizing agents, Thiazolidinediones, are PPARγ agonists that improve many of the symptoms of PCOS. Magnolol is a natural PPARγ agonist that improves insulin sensitivity in experimental models. Using a dehydroepiandrosterone (DHEA)-induced rat model of PCOS and IR, we aim to explore both the potential beneficial effect and the molecular mechanisms of action of Magnolol. Post-pubertal female Sprague Dawley rats injected subcutaneously with DHEA (6mg/100g body weight) for 28 days exhibited a significant increase in body weight as compared to age- and weight-matched controls. The DHEA-injected rats developed an increased number of cystically dilated follicles with thicker granulosa compared to control. PCOS rats showed statistically significant elevated serum levels of Luteinizing hormone and fasting insulin; with an increased Homeostatic Model Assessment Index of insulin resistance (HOMA-IR) as compared to control. Compared to control, PCOS rats had a significant lower ovarian protein expression of peroxisome proliferator activated receptor gamma (PPARγ), insulin receptor substrate 1 (IRS1), and protein kinase B (Akt) by Western Blot. Conversely, the PCOS group showed an increased mammalian target of rapamycin (mTOR) pathway activity as evident by an increase protein expression of phosphorylated mTOR as compared to control. When treated for 28 days with oral Magnolol (500mg/kg), the DHEA-induced PCOS rats showed a statistically significant decrease in body weight and serum LH levels as compared to the non-treated PCOS rats, but not to control rats. The number of cystically dilated follicles in the Magnolol-treated PCOS rats was significantly reduced compared to the PCOS rats not treated with Magnolol. In the Magnolol-treated PCOS rats the ovarian protein expression of PPARγ, IRS1 and Akt was significantly increased, while the mTOR expression was decreased compared to the non-treated PCOS group. In conclusion, Magnolol ameliorates the DHEA-induced PCOS phenotype histologically, hormonally and metabolically. Fundamentally, this work explores the elusive pathophysiologic association between IR and PCOS, by targeting pathways common to both disorders.