Nanoparticle-Delivered Rutin Prevents Metabolic and Oxidative Imbalance in Obesity Triggered by a High-Fat Diet: In Vivo and In Silico Studies

<b>Background:</b> Obesity, characterized by an abnormal and excessive accumulation of fat, significantly affects health by increasing the probability of chronic diseases and has become a pressing global health issue. Among natural compounds with therapeutic potential, rutin exhibits diverse biological effects, such as antioxidant, anti-inflammatory, and hypolipidemic properties. <b>Objective:</b> The purpose of this work is to evaluate the preventive effects of rutin loaded on chitosan nanoparticles on metabolic and oxidative alterations in male albino rats fed a high-fat diet (HFD). <b>Method:</b> The rats were allocated to four distinct groups: control, HFD, HFD treated with 50 mg/kg rutin, and HFD treated with 50 mg/kg nano-rutin, respectively, for six weeks. Results: Molecular docking analysis revealed that rutin exhibits an inhibitory interaction with PPAR-γ, suggesting its potential role in suppressing adipogenesis and contributing to its preventive effect against obesity. Nano-rutin markedly improved glycemic control, reducing fasting glucose from 161.75 ± 8.37 mg/dL in the HFD group to 133.50 ± 3.55 mg/dL, compared to 92.17 ± 3.53 mg/dL in controls. Serum leptin levels decreased from 28.95 ± 1.06 ng/mL in the HFD group to 15.58 ± 0.65 ng/mL with nano-rutin, approaching the control value of 10.43 ± 0.80 ng/mL. Oxidative stress was also significantly alleviated, as shown by a reduction in malondialdehyde (MDA) from 8.43 ± 0.20 U/µL in HFD rats to 6.57 ± 0.08 U/µL with nano-rutin, versus 1.29 ± 0.13 U/µL in controls. <b>Conclusions:</b> Rutin loaded on chitosan nanoparticles demonstrated protective effects against high-fat diet-induced obesity, mainly through modulation of leptin signaling and oxidative stress pathways. These findings highlight the promise of nano-rutin as a natural agent for preventing metabolic disorders related to obesity.