Lycopene Modulates Glycerophospholipid Metabolism and Promotes N‐Acylethanolamine Production to Alleviate Obesity

Obesity is often associated with dysregulated glycerophospholipid metabolism. Lycopene is known for its anti-obesity properties. However, the mechanism by which lycopene affects glycerophospholipid metabolism in obesity remains unclear. Here, a lycopene small intestinal sustained-release system (SR-Ly) was designed. Subsequently, SR-Ly was used to interfere with fatty liver caused by high-fat diet in mice. SR-Ly exhibited high encapsulation efficiency, stability, and sustained release, significantly enhancing lycopene's bioavailability. Moreover, treatment with SR-Ly resulted in reduced body weight gain in obese mice. Lipidomic analysis revealed significant modulation of glycerophospholipid pathways with lycopene increasing beneficial glycerophospholipids. Correlation-based analysis further suggested that lycopene may promote the conversion of N-acyl phosphatidylethanolamine to N-acylethanolamines (NAE), highlighting a possible metabolic route of interest. Structural equation modeling supported the association between lycopene intervention and improved glycerophospholipid metabolism. Additionally, compared to lipid oxidation, it was verified at both the gene and protein levels that lycopene has a greater positive effect on lipid synthesis in the mouse liver. Hence, SR-Ly is a promising therapeutic approach for fatty liver, effectively targeting glycerophospholipid metabolism. PRACTICAL APPLICATION: SR-Ly enhanced lycopene's stability, bioavailability, and sustained release. SR-Ly reduced body weight gain and modulated glycerophospholipid metabolism. Lycopene promoted N-acyl phosphatidylethanolamine conversion to N-Acylethanolamines. Lycopene improved glycerophospholipid metabolism, favoring lipid synthesis over oxidation.