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.

Background/Objectives: High-fat diet (HFD) feeding disrupts systemic metabolism and hypothalamic mechanisms that coordinate energy balance. Whether quercetin modifies the coordinated transcriptional systems linking m6A-related regulation with leptin-insulin and melanocortin 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, oral glucose tolerance, visceral adiposity, serum lipids, and terminal tissue measures were evaluated. Hypothalamic expression of 21 transcripts spanning m6A regulation, leptin-insulin signaling, melanocortin-associated genes, and oxidative response was quantified by RT-qPCR. Gene-level inference was complemented by principal component analysis, PERMANOVA, module-level analyses, bootstrap resampling, leave-one-sample-out sensitivity testing, and treatment-adjusted gene-gene covariance. 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. Sixteen of 21 transcripts met the predefined robustness criteria for the HFD + quercetin versus HFD contrast. PC1 and PC2 captured 73.5% of transcriptional variance, and the four groups differed in global molecular structure (PERMANOVA R² = 0.628, p = 0.0001). All three predefined transcriptional modules showed robust HFD + quercetin versus HFD differences. Conclusions: Quercetin attenuated major metabolic consequences of HFD feeding and was accompanied by coordinated hypothalamic transcriptional remodeling across m6A-regulatory, leptin-insulin, and melanocortin-associated domains. These data identify a transcriptional network for mechanistic follow-up without implying direct measurement of m6A activity or pathway activation.

Obesity contributes to an increase in the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and is diagnosed when hepatic steatosis is accompanied by at least one of the following factors: obesity or overweight, diabetes mellitus, or signs of metabolic abnormalities. MAFLD is a term that encompasses a wide range of liver disorders, ranging from simple steatosis to metabolic steatohepatitis, which can progress to cirrhosis and eventually, hepatocellular carcinoma (HCC). Lipotoxicity generated by a high-fat diet causes liver inflammation, therefore, blocking inflammatory pathways is considered a promising strategy to prevent MAFLD progression. Inflammatory responses and oxidative stress are linked to endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR) pathway. Although drugs such as resmetirom and semaglutide have recently been approved for the treatment of MAFLD, there is still a need to identify complementary therapies with different mechanisms of action. In this context, the present study evaluated the hepatoprotective effect of ellagic acid through the modulation of mRNAs of proteins in the UPR-Perk pathway in a murine model fed a high-calorie diet. This study revealed that the high-calorie diet activated the UPR pathway in response to stress, increasing the expression of the Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 genes in the liver and epididymal adipose tissue. Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin, and could therefore be considered a hepatoprotective agent.

Background: The NLRP3 inflammasome is a key driver of obesity-associated chronic low-grade inflammation, contributing to hypothalamic neuroinflammation and disruption of energy homeostasis. Quercetin, a bioactive flavonoid, has been proposed as a modulator of inflammatory and metabolic pathways, including the fat mass and obesity-associated gene (FTO). Objective: This study evaluated the effects of quercetin on hypothalamic mRNA expression of Fto and components of the TNF-α/NF-κB/NLRP3 pathway. Methodology: In a high-fat diet (HFD)-induced obesity model, male Wistar rats (n = 18) were divided into three groups: standard diet (SD), HFD, and HFD + Q (supplemented with quercetin 50 mg/kg/day for 12 weeks). Gene expression was analyzed by quantitative PCR using the 2^−ΔΔCt method. Results: HFD significantly increased the expression of Fto and pro-inflammatory genes, including Tnf, Nlrp3, Casp1, Il1b, and Il18. Quercetin supplementation attenuated this upregulation, restoring expression levels toward baseline. Conclusions: These findings indicate that quercetin reduces hypothalamic neuroinflammation and modulates Fto expression, likely through inhibition of NF-κB signaling and suppression of NLRP3 inflammasome activation. Quercetin may represent a potential molecular modulator of obesity-associated neuroinflammatory processes.