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

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.