2025-P: Protective Effects of Orlistat against High-Fat Diet-Induced Metabolic Disorders in Mice

Background: Accumulating evidence indicates that alterations of gut microbiota and metabolites have been involved in obesity and diabetes. Orlistat, a reversible inhibitor of pancreatic and gastric lipase, has beneficial effects on metabolism. However, the mechanism of its action is less understood. Methods: Metabolic indices, including weight, glucose tolerance and plasma lipids were determined in WT (C57BL/6J mice), HFD and HFD + ORL group. The effects of orlistat on gut microbiota and circulating metabolites in mice were assessed by 16S rRNA gene sequencing from fecal samples and LC-MS/MS from plasma samples. Results: Compared to HFD group, HFD + ORL group showed improvements in glucose tolerance and plasma cholesterol, and a distinct microbiota composition with a dominance of Rhodococcus and Pseudomonas on genus level, positively associated with ether lipid metabolism, fatty acid metabolism, α-linolenic acid metabolism and GnRH signaling pathway etc. Furthermore, metabolic perturbations caused by HFD were improved in the HFD + ORL group and were presented in PLS-DA analysis. The discrepant metabolites were involved in several metabolic pathways, such as alanine, aspartate and glutamate metabolism, as well as histidine metabolism etc. Intriguingly, fecal microbiome and metabolome results share two common metabolic pathways, linoleic acid metabolism and arachidonic acid metabolism. Conclusion: Our study suggests that orlistat may exert protective effects against metabolic disorders through modulating gut microbiota, which was involved in some common metabolic pathways with metabolome. Disclosure J. Ke: None. Y. An: None. B. Cao: None. D. Zhao: None.