Quercetin-Loaded Avocado Oil Nanoemulsion Reverses High-fat and High-carbohydrate Diet-Induced Testicular Dysfunction: Role of Oxidative Stress and NPY Signaling in a Randomized Trial.

Background: High-fat and high-carbohydrate diets (HF) can negatively affect male reproductive function, impairing spermatogenesis and testosterone production. Quercetin (Qu) may mitigate testicular damage, but its effectiveness is limited by poor bioavailability. Avocado oil (AO) improves blood lipid levels and enhances the absorption of fat-soluble nutrients. Objectives: We explore the impact of AO combined with quercetin on weight gain, dyslipidemia, hormonal dysregulation, testicular oxidative stress, and NPY signaling, all induced by a HF diet, to highlight testicular dysfunction and metabolic disorders. Methods: A nanoemulsion of avocado oil containing quercetin (NAOQu) was developed as an oil-in-water (O/W) nanoemulsion, utilizing the hydrophilic-lipophilic balance (HLB) value and conducting stability assessments, followed by characterization (DLS, Zeta potential, and TEM). Thirty rats were fed an HF diet for 8 weeks and treated with either Qu, a nanoemulsion of avocado oil (NAO), or NAOQu. Body weight was determined, and serum was analyzed for triglycerides (TG), cholesterol, HDL, and testosterone levels. Testicular homogenates were assessed for malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) activity, and cholesterol. Hypothalamic NPY mRNA expression was quantified using qPCR. Results: The NAOQu (1% Qu, 1:1 avocado: Coconut oil) exhibited a stable, spherical morphology with a particle size of 286.7 nm, a zeta potential of -25.8 mV, and enhanced physical stability. The NAOQu significantly reduced body weight, improved lipid profiles (lowering TG and cholesterol while increasing HDL), and restored testosterone levels by 85% compared to high-fat diet (HFD) controls and reduced testicular MDA by 62% while increasing GSH and SOD activities by 2.3-fold and 1.8-fold, respectively. Molecular analyses revealed decreased testicular cholesterol levels and downregulated NPY mRNA expression, indicating reduced metabolic stress. Conclusions: The combined NAOQu formulation showed greater protective effects than Qu or AO alone, suggesting a synergistic effect. These findings highlight the potential of avocado oil-based nanoemulsion as an effective delivery system for Qu, offering a novel therapeutic strategy to counteract HF-induced male reproductive dysfunction and metabolic disease.