Obesity caused by poor eating habits has become a global public health issue and harms human health. Rosmarinic acid (RA) is a natural active substance with many biological functions like antioxidant. However, the function of RA’s lipid-lowering effect and mechanism are not entirely clear. This study aimed to explore the effect of RA on obesity and its action mechanism in Caenorhabditis elegans. RA not only alleviated intestinal inflammation and change the composition of unsaturated fatty acid, but also decreased fat storage and adjusted the size and quantity of fat droplets without threatening development and reproduction or affecting energy intake. In addition, RA improved the integrity of intestinal barrier function in C. elegans. RNA sequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) comprehensively revealed that the lipid-lowering mechanism mediated by RA might involve lipid metabolism and anti-inflammatory pathways. Among them, RA regulates lipid metabolism by reducing fat synthesis through SBP-1 and increasing fatty acid β-oxidation via NHR-49. Furthermore, the anti-inflammatory pathway was associated with RA’s enhancement of the ratio of unsaturated fatty acid and alleviation of inflammatory reactions caused by Pseudomonas aeruginosa (PAO1). Therefore, RA regulated lipid metabolism and relieved inflammation, which had the potential for dietary supplements or functional foods.
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