Woxuanzhongzhou formula improves DHEAS and high-fat diet-induced IR and anovulatory mice via AMPK/PGC1- α/Irisin pathway.

Background: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women of reproductive age. Anovulation is one of the most important clinical features of PCOS, and insulin resistance (IR) is one of the critical pathogenic factors. Woxuanzhongzhou (WXZZ) is a traditional herbal formulation that has shown efficacy in treating PCOS combined with IR, but the underlying mechanism is not clear. The aim of this study was to investigate the molecular mechanism of WXZZ on dehydroepiandrosterone sulfate and high fat diet induced PCOS with IR mice.

Methods: 40 female C57BL/6 mice were randomized to 4 groups: control group, model group, metformin group, and WXZZ group. Some mice is induced by dehydroepiandrosterone sulfate (DHEA) and high-fat diet (HFD) for 3 weeks. Following model induction, metformin and WXZZ were administered by gavage. Body weight, fasting blood glucose (FBG), fasting insulin (FINS) levels, the homeostatic model assessment of insulin resistance (HOMA-IR), and gonadal hormones were measured. Estrous cycles were monitored. The structure of the gastrocnemius muscle and subcutaneous fatty tissue were also evaluated. Additionally, serum irisin and non-esterified fatty acids (NEAF) levels and the protein and gene expression levels of AMPK, PGC1-α, FNDC5, irisin in the gastrocnemius muscle and CaMKK, AMPK, PGC1-α, UCP1 in fat were analyzed.

Results: The DHEA + HFD + WXZZ group exhibited significant improvements in several key parameters compared to the DHEA + HFD group. WXZZ ameliorated endocrine and metabolic disorders, resumed estrous cycle in DHEAS and high-fat diet-induced IR and anovulatory mice. Significant reductions were observed in body weight, serum testosterone, luteinizing hormone, luteinizing hormone/ follicle-stimulating hormone ratio, FINS, and HOMA-IR. Additionally, WXZZ promoted irisin expression and secretion by up-regulating the protein and gene AMPK/PGC1-α/FNDC5 expression in gastrocnemius muscle and up-regulated the protein and gene CaMKK/AMPK/PGC1-α/UCP1 expression in fat. WXZZ inhibited the overproduction of serum NEFA, and reduced lipid accumulation. Structural analysis of the gastrocnemius muscle and adipose tissue revealed partial restoration.

Conclusion: WXZZ exhibits therapeutic effects in DHEAS and high-fat diet-induced IR and anovulatory mice. These effects may be mediated through the activation of AMPK/PGC1-α pathway in muscle to promote the secretion of irisin.