Dose-Responsive Effects of Garcinia mangostana Pericarp Extract on Metabolic Dysfunction, Redox Homeostasis, Adipokine Signaling, and Multiorgan Injury in High-Fat-Diet-Induced Obese Rats

Background: With its steadily rising global prevalence posing a profound public health challenge, obesity represents a complex disorder sustained by reciprocal disturbances in energy partitioning, glycemic control, adipokine–neuroendocrine signaling, cellular redox equilibrium, and organ integrity. The aim of this study was to evaluate the dose-dependent therapeutic effects of Garcinia mangostana pericarp extract (GME) in a high-fat-diet (HFD)-induced obesity model, focusing on adipokine patterns, redox balance, organ injury, and hepatic Nrf2/HO-1 levels. Methods: Sixty-four male Wistar albino rats were allocated into a 16-week 2 × 4 factorial design (n = 8/group): standard basal diet or 60%-kcal fat HFD, each concurrently administered vehicle or GME via daily oral gavage at 100, 200, or 300 mg/kg. Somatic growth parameters and fasting glycometabolic indices (glucose, insulin, HOMA-IR) were quantified. Circulating lipids, hepatorenal injury enzymes, regulatory peptides (spexin, asprosin, adiponectin, BDNF, irisin, GLP-1), and systemic/tissue redox markers (TAS, TOS, OSI, MDA, 4-HNE, 8-OHdG, enzymatic antioxidants) were determined via automated clinical chemistry analyzers, spectrophotometry, and specific ELISA kits. Hepatorenal histopathology, epididymal adipocyte morphometry, and hepatic nuclear Nrf2 and HO-1 abundance were quantitatively analyzed. Statistical evaluations were conducted using two-way factorial ANOVA assessing diet, treatment, and diet-by-treatment interactions, followed by Tukey’s post hoc test for multiplicity-adjusted comparisons (p < 0.05). Results: HFD feeding significantly increased final body weight, energy intake, fasting glucose, and marked insulin resistance (HOMA-IR: 7.89 vs. 1.69; p < 0.001), precipitating atherogenic dyslipidemia and hepatorenal injury relative to controls. This pathophysiology coincided with elevated circulating asprosin, alongside marked depletion of spexin, adiponectin, BDNF, enzymatic antioxidant defenses (SOD, CAT, GPx; all p < 0.001), and Nrf2/HO-1 levels. GME produced dose-dependent improvements across these metabolic disturbances (diet × treatment interaction: p < 0.001 for all primary outcomes). Relative to HFD controls, the 300 mg/kg dose reduced final body weight by 15.3% (p < 0.05), HOMA-IR by 69.5% (p < 0.001), triglycerides by 47.6% (p < 0.001), serum MDA by 55.4% (p < 0.001), and adipocyte diameter by 49.1% (p < 0.001), providing the most prominent improvements in hepatic steatosis, renal injury scores, and upregulation of nuclear Nrf2 (3.81-fold) and liver HO-1 (4.74-fold). Conversely, the 200 mg/kg dose was distinguished by maximizing neurotrophic support (peak BDNF elevation, +84.8% vs. HFD controls; p < 0.05) and effectively restoring circulating metabolic peptides (spexin and adiponectin) toward physiological levels. Conclusions: These findings indicate that GME supplementation dose-dependently attenuates high-fat-diet-induced metabolic dysfunction, a response accompanied in part by a concomitant reduction in daily energy intake. Among the evaluated regimens, the 300 mg/kg dose exhibited the most potent efficacy in improving glycemic control (HOMA-IR), circulating lipid profiles (triglycerides, total cholesterol, LDL-C), and parenchymal organ injury (hepatic steatosis and renal vacuolation). In contrast, the 200 mg/kg dose was distinguished by optimizing neurotrophic support and restoring suppressed adipokines toward physiological concentrations. Consequently, GME is anticipated and considered to provide valuable support to medical nutrition therapy and clinical dietetic management as a promising functional nutraceutical for counteracting diet-induced metabolic abnormalities; prospective clinical trials remain necessary to establish safety, bioavailability, and therapeutic dosing.