Fatty Acid Esters of Hydroxy Fatty Acids (FAHFA) Derivatives as Dual Modulators of Lipid Metabolism and Gut Microbiome in Obesity

Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs), endogenous lipids with anti-inflammatory and metabolic benefits, face challenges in clinical translation due to instability and high synthesis costs. This study introduces a scalable synthetic platform to engineer novel FAHFA derivatives with enhanced stability through bioisosteric modifications (e.g., amide, triazole bonds). Screening identified 12-TAASA and 12-HDTZSA as lead compounds, demonstrating potent inhibition of lipid uptake in hepatic cells without compromising glucose absorption. In a diet-induced obesity mouse model, oral administration of these derivatives reduced weight gain, improved glucose tolerance, and attenuated ectopic lipid deposition, rivaling the efficacy of semaglutide. Mechanistically, 12-TAASA and 12-HDTZSA remodeled the gut microbiome by enriching SCFA producing taxa. 12-TAASA also suppressed intestinal lipid absorption via transcriptomic regulation of key genes. These findings position synthetic FAHFAs as dual-action therapeutics, targeting both host lipid metabolism and gut microbiota dysbiosis, offering a promising strategy for obesity and metabolic disorders.