Marine n‐3 Polyunsaturated Fatty Acids Mitigate Obesity Traits Through PRDM16‐Driven Gene–Nutrient Interaction and Spatiotemporal Scale Browning Process

ABSTRACT Marine n‐3 polyunsaturated fatty acids (PUFAs) as functional lipids are pivotal in controlling obesity but the mechanism is poorly understood. Herein, we unravel the role of n‐3 PUFAs in mitigating obesity traits through gene–nutrient interactions and white‐to‐brown adipose conversion. Data from 45,664 UK Biobank participants followed for 8.7 years were analyzed using Cox proportional hazards regression. The metabolites of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)‐treated adipocytes during different spatiotemporal stages were measured by high‐resolution mass spectroscopy. Habitual fish oil consumption was associated with 12% and 7% lower risk of obesity and high body fat percentage, respectively. Notably, fish oil had significant interactions with the variants of PRDM16 at rs60330317, rs2493212, rs2483239, and rs2297828. DHA and EPA supplementation reduced body weight and serum total cholesterol level in diet‐induced obese mice. Metabolomics profiling of subcutaneous adipose tissue revealed that both DHA and EPA significantly decreased the concentrations of glutamic acid and glutamine while enhancing glutathione. The spatiotemporal metabolomics further revealed that DHA/EPA mainly manipulates the metabolites involved in white‐to‐brown adipose conversion. Consistently, DHA and EPA treatments induce browning process, reduce the formation of lipid droplets, and promote mitochondrial function during the differentiation of adipocytes. Mechanistically, n‐3 PUFAs suppressed PPARγ acetylation and PRDM16 ubiquitination while knocking down the expression of PRDM16 that blocked the browning effect. In addition, they downregulate the expression of miRNA‐378a and miRNA‐34a. These findings indicate that DHA and EPA prevent adiposity by promoting adipocyte browning in the PRDM16‐dependent way and support the use of fish oil supplements as a preemptive therapy for obesity control.