Acute aerobic exercise reveals that FAHFAs distinguish the metabolomes of overweight and normal-weight runners

Alisa B Nelson, Lisa S Chow, David B Stagg, Jacob R Gillingham, Michael D Evans, Meixia Pan, Curtis C Hughey, Chad L Myers, Xianlin Han, Peter A Crawford, Patrycja Puchalska, Alisa B Nelson, Lisa S Chow, David B Stagg, Jacob R Gillingham, Michael D Evans, Meixia Pan, Curtis C Hughey, Chad L Myers, Xianlin Han, Peter A Crawford, Patrycja Puchalska

Abstract

BackgroundResponses of the metabolome to acute aerobic exercise may predict maximum oxygen consumption (VO2max) and longer-term outcomes, including the development of diabetes and its complications.MethodsSerum samples were collected from overweight/obese trained (OWT) and normal-weight trained (NWT) runners prior to and immediately after a supervised 90-minute treadmill run at 60% VO2max (NWT = 14, OWT = 11) in a cross-sectional study. We applied a liquid chromatography high-resolution-mass spectrometry-based untargeted metabolomics platform to evaluate the effect of acute aerobic exercise on the serum metabolome.ResultsNWT and OWT metabolic profiles shared increased circulating acylcarnitines and free fatty acids (FFAs) with exercise, while intermediates of adenine metabolism, inosine, and hypoxanthine were strongly correlated with body fat percentage and VO2max. Untargeted metabolomics-guided follow-up quantitative lipidomic analysis revealed that baseline levels of fatty acid esters of hydroxy fatty acids (FAHFAs) were generally diminished in the OWT group. FAHFAs negatively correlated with visceral fat mass and HOMA-IR. Strikingly, a 4-fold decrease in FAHFAs was provoked by acute aerobic running in NWT participants, an effect that negatively correlated with circulating IL-6; these effects were not observed in the OWT group. Machine learning models based on a preexercise metabolite profile that included FAHFAs, FFAs, and adenine intermediates predicted VO2max.ConclusionThese findings in overweight human participants and healthy controls indicate that exercise-provoked changes in FAHFAs distinguish normal-weight from overweight participants and could predict VO2max. These results support the notion that FAHFAs could modulate the inflammatory response, fuel utilization, and insulin resistance.Trial registrationClinicalTrials.gov, NCT02150889.FundingNIH DK091538, AG069781, DK098203, TR000114, UL1TR002494.

Keywords: Adipose tissue; Diabetes; Metabolism; Obesity.

Conflict of interest statement

Conflict of interest: PAC has served as an external consultant for Pfizer Inc., Abbott Laboratories, and Janssen Research & Development.

Figures

Figure 1. Study design and untargeted metabolomics…
Figure 1. Study design and untargeted metabolomics analytical pipeline.
(A and B) Scatter plots of maximal oxygen consumption (VO2max) against BMI and percent body fat. Strength of correlation expressed as Pearson correlation coefficient (R). n = 25. (C) Schematic of study design and sample collection time points. (D) Schematic of analytical pipeline for data acquisition. ***P < 0.001, ****P < 0.0001. NWT, normal weight trained runners; OWT, overweight/obese trained group; IS, internal standard; Phe, phenylalanine; Val, valine; βOHB, β-hydroxybutyrate; RP, reverse phase chromatography; ESI, electrospray ionization; (+), positive mode; (–), negative mode; HILIC, hydrophilic interaction chromatography; CD 2.0, Compound Discoverer version 2.0; MS/MS, tandem mass spectrometry.
Figure 2. Summary of untargeted metabolomics differential…
Figure 2. Summary of untargeted metabolomics differential analysis.
(A–D) Metabolic profile differential analysis summary and PCA for 4 group comparisons: exercise effect in NWT (A); exercise effect in OWT (B); BMI effect at baseline serum conditions (C); BMI effect immediately after running (D). Blue arrow, decreasing abundance after exercise/OWT; red arrow, increasing abundance after exercise/OWT. Venn diagrams represent overlapping m/z and retention time pairs in NWT versus OWT and pre versus post analyses. Percentages on PCA axes represent fraction of explained variance captured by first 2 principal components (Dim1, Dim2). Points inside PCA represent individual samples. Spheres represent normal distribution of group clusters, added after unsupervised PCA analysis in R (FactoMineR and Factoextra packages). (E and F) Euclidean distance of individual NWT (Dim1, Dim2) and OWT (Dim1, Dim2) from intragroup centroids compared with distance of all individuals from center of all points (denoted H0, as the null hypothesis) for preexercise metabolic profile (E) and postexercise metabolic profile (F). (G) Euclidean distance of OWT individuals (Dim1, Dim2) from center of NWT cluster before and after exercise. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001, by Student’s t test. Data represent mean ± SEM.
Figure 3. Exercise-induced metabolic profiles correlate with…
Figure 3. Exercise-induced metabolic profiles correlate with circulating cytokines in OWT.
(A) Fold change in concentration of circulating MCP-1 and TNF-α in OWT samples relative to NWT; significance symbols without bracket show OWT/NWT comparison, while symbol with bracket shows effect of exercise. (B) Fold change in concentration of circulating cytokines relative to before exercise; significance symbol shows pre- to postexercise comparison. (C and D) Pearson correlation coefficients of 152 intersecting putative metabolites from exercise-related NWT (C) and OWT (D) profiles against IL-6, MCP-1, and IL-10. Putative metabolites are ordered by m/z. *P ≤ 0.05 by Student’s t test. N = 6 per group. Data represent mean ± SEM.
Figure 4. Validation of analytical pipeline.
Figure 4. Validation of analytical pipeline.
(A) Abundances of putative acylcarnitine (AC) species in NWT and OWT groups relative to their respective preexercise abundance. (B) Postexercise abundance of βOHB in NWT and OWT groups relative to their respective preexercise abundance, identified by internal standard. (C) Abundances of putative free fatty acid (FFA) species in NWT and OWT groups relative to their respective preexercise abundance. Significance symbols (A–C) denote pre- to postexercise comparison; symbols with brackets denote NWT to OWT comparison. (D) Putative purine nucleoside abundance in OWT before and after exercise relative to NWT level; significance symbols indicate OWT to NWT comparison. (E–G) Scatter plot baseline abundance of inosine for NWT (black circles) and OWT (blue squares) groups against percent body fat (E), VO2max (F), and s.c. fat (G). R value of correlation pre- and postexercise (NWT + OWT) abundance to study measurements; significance symbols denote comparison to Pearson correlation R = 0. Putative species identified by m/z and MS/MS fragmentation. *P ≤ 0.05; ¥P ≤ 0.01; #P ≤ 0.001; ‡P ≤ 0.0001 by Student’s t test with Benjamini-Hochberg correction for multiple testing. Data represent mean ± SEM.
Figure 5. FAHFAs decrease in serum with…
Figure 5. FAHFAs decrease in serum with acute aerobic exercise in NWT but not OWT.
(A) OWT baseline concentration of circulating FAHFAs relative to NWT; significance symbols indicate OWT/NWT comparison. (B) Exercise effect on FAHFA concentration relative to preexercise in NWT and OWT; significance symbols indicate pre- to postexercise comparison. *P ≤ 0.05; ¥P ≤ 0.01; #P ≤ 0.001; ‡P ≤ 0.0001 by Student’s t test with Benjamini-Hochberg correction for multiple testing. Data represent mean ± SEM. (C) Pearson correlation coefficient of fat mass measurements, circulating insulin, and HOMA-IR scores against baseline FAHFA concentrations in NWT and OWT. (D) Pearson correlation coefficient of exercise-induced changes in FAHFAs versus IL-6; significance symbols indicate difference in Pearson correlation between NWT and OWT. Significance determined by adjusted P value (q) after computed Fisher Z score. *q ≤ 0.05; ¥q ≤ 0.01; #q ≤ 0.001 by Student’s t test. Error bars represent 95% confidence intervals.
Figure 6. BMI and visceral fat impact…
Figure 6. BMI and visceral fat impact FAHFA turnover after acute running in trained groups.
(A and B) Regression coefficients with 95% CI for impact of incremental BMI and fat mass measurements on fold-change (before to after exercise) of FAHFAs (A) and FFAs (B); significance symbols denote adjusted P value of relationship between fat depot and metabolite fold change. (C) Scatter plot true BMI versus predicted BMI after 5-fold cross-validation. (D) Scatter plot VO2max versus predicted after 5-fold cross-validation; significance symbol indicates comparison to Pearson correlation R2 = 0. (E and F) Median values with IQR of top positive and top negative coefficients from ridge regression predicting BMI (E) and VO2max (F). Median determined after 5 different models, 1 for each training set split (see Methods for details). *P ≤ 0.05; **P ≤ 0.01 by Student’s t test with Benjamini-Hochberg correction for multiple testing.

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