Maximal Fat Oxidation Testing in Gilbert’s Syndrome: Plasma Lipid-Mobilization Signatures from Untargeted Metabolomics

Background Gilbert’s syndrome (GS), defined by an unconjugated hyperbilirubinemia, has been linked to favorable metabolic traits, including greater fat oxidation and distinct metabolite profiles. Whether GS confers a different acute plasma metabolomic response to a FatMax test remains unknown. Methods A human age- and sex-matched case–control (GS vs normobilirubinemic controls) study was conducted from March 2023 to December 2023 at the University of Vienna. After a 12-h-overnight-fast 80 participants completed a FatMax test on a cycle ergometer and from 79 the plasma metabolome was analyzed. Blood samples were collected before (baseline) and immediately after exercise. An untargeted plasma metabolomics analysis was performed via LC–MS. Results GS and controls differed significantly in serum bilirubin concentrations (GS: 33.5 ± 13.3; C: 12.2 ± 2.72; p < 0.001, in µmol/L). Apart from the expected elevations in the subclass of bilirubin in GS, the global acute metabolomic response to FatMax was broadly similar between groups. Exercise-response was similar in all participants, displaying a fat-oxidation signature post-exercise (increase in several acetylcarnitines (dodecoanylcarnitine, tetradecenoyl carnitine, (10Z,13Z,16Z,19Z)-Docosatetraenoylcarnitine), and several fatty acids (especially unsaturated fatty acids)), with a total of 231 metabolites changing in response to exercise. Individuals with higher maximal fat oxidation displayed larger immediate post-exercise increases in selected metabolites, such as fatty acids. Conclusion A submaximal FatMax exercise test elicits a robust plasma signature consistent with fatty-acid mobilization and increased fatty-acid availability for oxidation. However, within the constraints of a 12-h fast and exercise at this workload and duration, GS did not demonstrate a distinct acute metabolomic response beyond elevations in bilirubins.