5‐Demethyl‐Polymethoxyflavones Mitigate Obesity by Reducing Adipose Tissue Inflammation, Promoting Browning, and Modulating Gut Microbiota in High‐Fat Diet‐Fed Mice

Given the escalating prevalence of obesity worldwide, identifying efficacious dietary components is crucial. This study investigated whether citrus-derived 5-demethyl-polymethoxyflavones (5-DPMFs) protect against obesity in high-fat diet (HFD)-induced obese mice. Male C57BL/6 mice were fed an HFD and supplemented with a citrus-derived powder (CP) containing 5-DPMFs as the main bioactive components. Two doses of CP (0.25% and 1% in the diet) were tested, corresponding to approximately 36 and 145 mg/kg body weight of 5-DPMFs, respectively. Key adipose tissue parameters were assessed, including inflammatory cytokines and browning markers associated with p38 MAPK signaling. Treatment with 5-DPMFs significantly attenuated adipose tissue inflammation, as evidenced by reduced levels of MCP-1, TNF-α, IL-6, and IL-1β. Concurrently, fat browning was enhanced by upregulating thermogenic and mitochondrial proteins. Gut microbiota analysis revealed that 5-DPMFs increased the relative abundance of beneficial probiotic species, such as Lactobacillus and Limosilactobacillus reuteri, which have been linked to improved metabolic profiles. These findings demonstrate that 5-DPMFs mitigate obesity-associated adipose inflammation, promote the browning of white adipose tissue (WAT), and favorably regulate gut microbiota composition in HFD-fed mice. Our results suggest that 5-DPMFs could serve as a functional food ingredient for obesity prevention and management.