Methionine restriction improves lipid metabolism disorders and enhances immunity in obese mice through liver lipid remodeling.

Background: Methionine-restriction diet (MRD) has been reported to improve obesity-related metabolic disorders, but its effects during weight loss and the underlying mechanisms remain unclear. This study investigated whether reducing dietary methionine could improve metabolic status, reshape lipid composition, and influence inflammatory and antibacterial responses in high-fat diet (HFD) induced obese mice. Methods: Male C57BL/6 mice were fed a high-fat diet for 16 weeks to induce obesity and were then assigned to continued HFD, a normal control diet (NC), or a MRD for 21 days. Body weight, food and water intake, tissue mass, and serum biochemical indices were measured. Targeted metabolomics and lipidomics of liver and serum were performed by liquid chromatography-mass spectrometry. Serum inflammatory factors were determined by enzyme-linked immunosorbent assay, and resistance to bacterial infection was evaluated using a Results: Both the NC and MRD reduced body weight and epididymal fat mass compared with the continuous HFD, whereas routine serum biochemical indices showed no significant differences between the two diet-switch groups. Targeted metabolomics revealed only limited differences between the MRD and NC groups in both liver and serum, suggesting that MRD did not induce broad metabolic disturbance during weight loss. In contrast, lipidomics showed clear lipid remodeling, especially in the liver, characterized by increased phosphatidylethanolamine and phosphatidylserine and decreased phosphatidic acid, lysophosphatidylcholine, and diacylglycerol, while total phosphatidylcholine remained largely unchanged. MRD also reduced the average acyl-chain length and saturation of hepatic phosphatidylethanolamine and phosphatidylcholine. Functionally, MRD reduced IL-1β and IL-6 compared with NC, whereas TNF-α was reduced in both diet-switch groups compared with HFD., as well as reduced bacterial burdens in the liver and spleen after Conclusion: These findings indicate that MRD during weight loss does not broadly disrupt systemic metabolism, but is associated with selective hepatic lipid remodeling and improved inflammatory and antibacterial responses. This study extends current understanding of dietary MRD by linking weight-loss intervention with liver lipid reorganization and host defense, and provides experimental support for nutritional strategies targeting obesity-related metabolic dysfunction.