Effects of total flavonoids from Eucommia ulmoides Oliv. leaves on polycystic ovary syndrome with insulin resistance model rats induced by letrozole combined with a high-fat diet

• Published in: Journal of ethnopharmacology 2021-06, Vol.273, p.113947, Article 113947
• Main Authors: Peng, Meng-fan, Tian, Shuo, Song, Ya-gang, Li, Cai-xia, Miao, Ming-san, Ren, Zhen, Li, Ming
• Format: Article
• Language: English
• Subjects: Animals; Body Weight - drug effects; Diet, High-Fat - adverse effects; Disease Models, Animal; Eucommia ulmoides Oliv. leaves; Eucommiaceae - chemistry; Female; Flavonoids - chemistry; Flavonoids - pharmacology; Flavonoids - therapeutic use; Gonadal Steroid Hormones - blood; Hypothalamus - drug effects; Hypothalamus pituitary ovary axis; Insulin Resistance; Insulin-Like Growth Factor I - metabolism; Kisspeptins - metabolism; Letrozole - toxicity; Metformin - pharmacology; Metformin - therapeutic use; Ovary - drug effects; Pancreas - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Pituitary Gland - drug effects; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Plant Leaves - chemistry; Polycystic ovary syndrome; Polycystic Ovary Syndrome - blood; Polycystic Ovary Syndrome - chemically induced; Polycystic Ovary Syndrome - drug therapy; Polycystic Ovary Syndrome - pathology; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Androgen - metabolism; Receptors, Leptin - metabolism
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2021.113947

Eucommia ulmoides Oliv. leaves are the dry leaves of Eucommia ulmoides Oliv. Modern studies have shown that Eucommia ulmoides Oliv. leaves and its extracts have many pharmacological effects, such as regulating hypothalamus pituitary ovary (HPO) axis function, estrogen like effects, correcting insulin resistance (IR), regulating lipids, and reducing weight, which are consistent with the clinical manifestations in polycystic ovary syndrome (PCOS) patients. PCOS patients often have HPO axis disorder, low estrogen, high androgen, high IR complication rate, and obesity. Previous preclinical studies have shown that total flavonoids from Eucommia ulmoides Oliv. leaves (TFEL) can improve the imbalance in sex hormone secretion in perimenopausal animal models by regulating the function of the HPO axis. Thus, it is important to understand if flavonoids are the active parts of Eucommia ulmoides Oliv. leaves that interfere with polycystic ovary syndrome with insulin resistance (PCOS-IR), and determine the regulatory role they play in sex hormones and IR? Investigate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the ovary and kisspeptin/insulin like growth factor/leptin receptor1/androgen receptor (Kiss1/IGF-1/LEPR/AR) in the HPO axis to determine the mechanism of TFEL intervention in a rat model of PCOS-IR model rats. A rat model of PCOS-IR was established using a high-fat diet (49 d) combined with letrozole (1 mg/kg·d, for 28 d). Then, metformin (300 mg/kg·d) and TFEL (220 mg/kg·d, 110 mg/kg·d, and 55 mg/kg·d) were administered continuously for 21 days. At the end of the experiment, samples were taken and the related indexes were measured. TFEL reduced the body weight, Lee's index, ovarian index, ovarian area and ovarian volume, increased serum E2, SHBG levels and ISI, decreased serum levels of T, LEP, INS, and FBG (whole blood), and reduced the HOMA-IR in rats with PCOS-IR. TFEL downregulate Kiss1, IGF-1, and AR in the arcuate nucleus of hypothalamus, and upregulate Kiss1, downregulate IGF-1 and AR in the pituitary gland, and upregulate Kiss1, downregulate IGF-1, LEPR, and AR in the ovary of rats with PCOS-IR. TFEL could downregulate p-IRS-1Ser307, upregulate IRS-1, p-IRS-1Tyr895, PI3Kp85α, p-PI3Kp85α, AKT, p-AKT, and GLUT4 in the ovary, and ameliorated histopathological changes in the ovary and pancreas of rats with PCOS-IR. TFEL can inhibit ovarian hyperplasia, regulate disorders of glucose and lipid metabolism and improve the s