Quercetin Attenuates Metabolic Dysfunction and Reshapes Hypothalamic m6A-Related, Leptin–Insulin, and Melanocortin-Associated Transcription in High-Fat-Diet-Fed Rats

Background/Objectives: High-fat diet (HFD) feeding disrupts systemic metabolism and hypothalamic mechanisms that coordinate energy balance. Whether quercetin modifies coordinated hypothalamic transcription linking m6A-related regulation with leptin–insulin- and melanocortin-associated biology remains unclear. We examined the metabolic and hypothalamic transcriptional response to quercetin during chronic HFD exposure. Methods: Male Wistar rats were studied for 16 weeks in a 2 × 2 factorial design: Control (n = 8), Control + quercetin (n = 5), HFD (n = 5), and HFD + quercetin (n = 6). Quercetin was administered orally at 100 mg/kg/day. Body weight, fasting glucose, food/fluid intake, calculated energy intake, oral glucose tolerance, terminal adiposity, lipids, and a 21-transcript hypothalamic RT-qPCR panel were evaluated. Analyses included factorial models with HC3 inference and FDR control, PCA/PERMANOVA, predefined transcriptional modules, bootstrap and leave-one-sample-out sensitivity analyses, treatment-adjusted covariance, and shrinkage regularization. Results: At week 16, HFD + quercetin reduced glucose AUC relative to HFD by 2415 mg·min/dL (q = 0.0029), visceral fat by 5.16 g (q = 0.004), and triglycerides by 47.03 mg/dL (q < 0.001), without a corresponding difference in final body weight. Diet × quercetin interactions were supported for week-16 AUC, visceral adiposity, triglycerides, and 15 of 21 hypothalamic transcripts. Sixteen of 21 transcripts met robustness criteria for the HFD + quercetin versus HFD contrast. PC1 and PC2 captured 73.5% of transcriptional variance, and all three predefined transcriptional modules showed robust diet-dependent responses. Regularized covariance sensitivity preserved the direction of all 210 treatment-adjusted transcript associations. Conclusions: The principal metabolic effects of quercetin were predominantly evident under HFD conditions and were accompanied by coordinated hypothalamic transcriptional remodeling across m6A-related, leptin–insulin-associated, and melanocortin-associated domains. These data define a transcriptional architecture for mechanistic follow-up without implying direct measurement of circulating leptin or insulin, m6A activity, protein abundance, or pathway activation.