Unraveling Tissue‐Specific Fatty Acid Biosynthesis and Inter‐Tissue Crosstalk in Mice through Stable‐Isotope Tracing Metabolomics

Abstract Biosynthesis of free fatty acids (FFAs) in mammals is pivotal for metabolic homeostasis, yet a comprehensive understanding of tissue‐specific biosynthesis and inter‐tissue crosstalk of FFAs remains incomplete. In vivo stable‐isotope tracing metabolomics is utilized to comprehensively measure FFA biosynthesis and inter‐tissue crosstalk in mice. Systematically assessing tissue‐specific biosynthesis of 13 FFAs across 15 tissues unveils dynamic spatial and temporal accumulation and redistribution of FFAs throughout the body. Employing an analytical framework to deconvolve mass isotopologue patterns, inter‐tissue crosstalk is explored for saturated, polyunsaturated, and monounsaturated FFAs, and quantify communications of FFA (16:0) and FFA (18:0) between the liver and other tissues. Then, a decline in fatty acid biosynthesis in peripheral tissues but not in the brain of aged mice is observed, particularly evident in palmitic acid and monounsaturated fatty acids. These findings illuminate the complex interplay between tissue‐specific fatty acid biosynthesis and the maintenance of metabolic homeostasis.