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

Abstract

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.