Evaluation of the Relationships of Fisetin and Atorvastatin with Adipokine, Hepatokine, Myokine Profiles and Metabolic Parameters in Rats Fed with High-Fat Diet

<title>Abstract</title> Objective The aim of this study is to evaluate the effects of fisetin and atorvastatin administration on metabolic parameters and adipokine, hepatokine, and myokine profiles in rats fed a high-fat diet (HFD). Additionally, the effects of these agents on liver and skeletal muscle histology were investigated. Methods In the study, male Sprague-Dawley rats were randomly divided into five groups: K(Control), Y(HFD), YF(HFD + Fisetin), YA(HFD + Atorvastatin) and YAF(HFD + Atorvastatin + Fisetin). The Y groups were fed a high-fat diet for 8 weeks. The intervention groups were administered fisetin (50 mg/kg/day) and atorvastatin (10 mg/kg/day) orally via gavage in addition to the high-fat diet for 8 weeks. At the end of the study, blood biochemistry, asprosin, fetuin-A, GDF-15, Metrnl, and histological changes in liver and gastrocnemius muscle tissue were examined. Results Histopathological examinations revealed significant structural damage in liver and muscle tissues in groups treated with HFD, while these damages were significantly reduced in the combined treatment group. However, limited effects were observed on LDL-C and TG levels in the biochemical data; an increase in total cholesterol, a decrease in glucose levels, and improvements in creatinine and urea levels were detected. No significant differences were observed in adipokine, hepatokine, and myokine levels between the groups. Conclusion The combination of fisetin and atorvastatin significantly reduced HFD-induced liver and muscle tissue damage at the histological level. In terms of biochemical parameters, the combination therapy may be protective at the tissue level, but its effects on metabolic regulation may be limited depending on the dose and duration. Therefore, pharmacodynamic interactions and optimal dosage should be investigated in more detail.