Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1-/- mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1-/- only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.

Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr Way Oakland CA 94609 United States of America

College of Medicine Department of Pharmacology and Experimental Therapeutics Louisiana State University Health Sciences Centre 1901 Perdido Str New Orleans United States of America

Department of Medical Research Taichung Veterans General Hospital No 1650 Sec 4 Taiwan Boulevard Taichung 407 Taiwan

Department of Pediatrics Tungs' Taichung MetroHarbor Hospital Taichung 435 Taiwan

Division of Endocrinology and Metabolism Center for Geriatrics and Gerontology Taichung Veterans General Hospital No 1650 Sec 4 Taiwan Boulevard Taichung 407 Taiwan

Faculty of Biochemistry and Molecular Medicine Biocenter Oulu University of Oulu P O Box 5400 FI 90014 Finland

Laboratory of Gnotobiology Institute of Microbiology Czech Academy of Science Novy Hradek 549 22 Prague Czech Republic

Laboratory of Lipid Biochemistry and Protein Interactions Campus Gasthuisberg KU Leuven Herestraat Box 601 B 3000 Leuven Belgium

Light Hall Dept of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville Tennessee 37232 0615 United States of America

Lyon University INSERM U1060 CarMeN Laboratory and CENS Claude Bernard University CRNH Rhône Alpes Centre Hospitalier Lyon Sud 69310 Pierre Bénite France

Medical Research Council Human Nutrition Research Elsie Widdowson Laboratory Fulbourn Road Cambridge CB1 9NL Affiliated with the University of Cambridge United Kingdom

NIHR BRC Core Metabolomics and Lipidomics Laboratory Level 4 Laboratory Block Cambridge University Hospitals University of Cambridge Cambridge UK

UMR CEA INRA Service de Pharmacologie et d'Immunoanalyse Laboratoire d'Immuno Allergie Alimentaire Université Paris Saclay F 91991 Gif sur Yvette France

University of Hohenheim Institute of Food Chemistry Garbenstrasse 28 D 70599 Stuttgart Germany

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