10-epi-PDX alleviates high-fat-diet-induced obesity by modulating lipid droplet dynamics and restoring metabolic balance

Obesity-associated metabolic dysfunction is driven by chronic inflammation and disrupted lipid metabolism, however the potential of lipid-derived regulatory mediators in counteracting these processes remains poorly understood. 10-epimer-protectin DX (10-epi-PDX), a novel epimeric derivative of protectin DX, has recently emerged as a promising modulator of metabolic and inflammatory pathways. In this study, we investigated the therapeutic efficacy and underlying mechanisms of 10-epi-PDX in a mouse model of diet-induced obesity. Administration of 10-epi-PDX significantly ameliorated obesity-related metabolic abnormalities, including excessive weight gain, hepatic steatosis, and adipose tissue inflammation. Furthermore, treatment with 10-epi-PDX markedly enhanced glucose tolerance and insulin sensitivity compared to vehicle-treated obese controls. Hepatic RNA sequencing revealed that 10-epi-PDX reprogrammed obesity-altered lipid metabolism by restoring the expression of key genes involved in lipid droplet formation, lipid transport, and steroid biosynthesis. These transcriptomic alterations closely paralleled the observed improvements in metabolic phenotypes. Collectively, this study provides the first evidence that 10-epi-PDX mitigates obesity-induced metabolic impairment through the coordinated regulation of inflammation and hepatic lipid metabolic pathways. These findings identify 10-epi-PDX as a novel lipid-derived regulator and highlight its potential as a therapeutic and nutraceutical candidate for obesity and its associated metabolic complications.