The year of 2023 displayed the highest average global temperatures since it has been recorded-the duration and severity of extreme heat are projected to increase. Rising global temperatures represent a major public health threat, especially to occupations exposed to hot environments, such as construction and agricultural workers, and first responders. Despite efforts of the scientific community, there is still a need to characterize the pathophysiological processes leading to heat related illness and develop biomarkers that can predict its onset. Here, we performed a plasma lipidomic analysis on male and female subjects who underwent heat tolerance testing (HTT), consisting of a 2-h treadmill walk at 5 km/h with 2% inclination at a controlled temperature of 40 deg C. We identified 995 lipids from 27 classes, with nearly half of all detected lipids being responsive to HTT. Lipid classes related to substrate utilization were predominantly affected by HTT, with a downregulation of triacylglycerols and upregulation of free fatty acids and acyl-carnitines (CARs). We additionally examined correlations between changes in plasma lipids by using the physiological strain index (PSI). Here, even chain CAR 4:0, 14:0 and 16:1, suggested by-products of incomplete beta oxidation, and diacylglycerols displayed the highest correlation to PSI. PSI did not correlate with plasma lactate levels, suggesting that correlations between even chain CARs and PSI is related to metabolic efficiency versus physical exertion. Overall, our results show that HTT has a strong impact on the plasma lipidome and that metabolic inefficiencies may underlie heat intolerance.

The authors have declared no competing interest.

The project was funded by the BRAVE Agile Investment from the Pacific Northwest National Laboratory and the Office of Naval Research, grant no. N0001411MP20023, USA. ESN was partially supported by NIDDK/R01DK138335.

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This study was performed in accordance with the World Medical Association, declaration of Helsinki and received approval from the Institutional Review Board (IRB) of the Uniformed Services University via protocol numbers: G191FY; FAM-81-3173-01.

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