Anti-Obesity Effects of Acid-Processed Citrus reticulata Blanco Peel Extract Enriched in Highly Bioactive Polymethoxyflavones: Inhibition of 3T3-L1 Adipocyte Differentiation and Therapeutic Efficacy in ob/ob Mice

<b>Background/Objectives</b>: Chronic diseases linked to obesity represent a major global health challenge. Although pharmaceutical treatments show efficacy, their use is often limited by side effects. <b>Methods</b>: This study investigated the anti-obesity effects of acid-processed <i>Citrus reticulata</i> Blanco peels extract (CRBE) prepared through reflux extraction with 50% ethanol, followed by acid treatment using 3 M hydrogen chloride and neutralization. <b>Results</b>: Following acid treatment, the composition of the extract showed a marked increase in the 5-demethylated forms of polymethoxyflavones, particularly 5-demethylnobiletin (31.86 mg/g) and 5-demethyltangeretin (34.68 mg/g), whereas the concentrations of the typical citrus polymethoxyflavones, nobiletin (14.82 mg/g) and tangeretin (10.61 mg/g), decreased. Using 3T3-L1 preadipocytes, CRBE inhibited adipogenesis concentration dependently, substantially decreasing the expression of adipogenic transcription factors and lipid metabolism-related proteins. In <i>ob</i>/<i>ob</i> mice, oral CRBE substantially suppressed body weight gain without affecting food intake, while normalizing liver function indicators and improving serum lipid profiles by reducing total cholesterol, triglycerides, and low-density lipoprotein. <b>Conclusions</b>: Acid-processed CRBE effectively inhibits adipocyte differentiation and exhibits anti-obesity effects in vivo, offering potential as a natural agent for obesity management with minimal side effects.