Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi, P. R.; Mellon, S. H.; Flory, J. D.; Abu-Amara, D.; Wolkowitz, O. M.; Yehuda, R.; Jett, M.; Marmar, C.; Hood, L.; Wang, K.; Lee, I.; Hammamieh, R.; Gautam, A.; Daigle, B. J.; Yang, R.; Doyle, F. J.

doi:10.1101/492827

bioRxiv · 10.1101/492827

Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit

Somvanshi, P. R.·Mellon, S. H.·Flory, J. D.·Abu-Amara, D.·Wolkowitz, O. M.·Yehuda, R.·Jett, M.·Marmar, C.·Hood, L.·Wang, K.·Lee, I.·Hammamieh, R.·Gautam, A.·Daigle, B. J.·Yang, R.·Doyle, F. J.

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Abstract

PTSD is associated with metabolic comorbidities; however it is not clear how the neuroendocrine disturbances affect metabolism. To analyze this we employed a systems biological approach using an integrated mathematical model of metabolism, HPA axis and inflammation. We combined the metabolomics, neuroendocrine, clinical lab and cytokine data from combat-exposed veterans with and without PTSD, to characterize the differences in regulatory effects. We used the pattern of fold change in metabolites representing pathway level differences as reference for metabolic control analysis (MCA) using the model. MCA revealed parameters constituting the HPA axis, inflammation and GPCR pathway that yielded metabolic dysfunction consistent with PTSD. To support this, we performed causal analysis between regulatory components and the significantly different metabolites in our sample. Causal inference revealed that the changes in glucocorticoid receptor sensitivity were mechanistically associated with metabolic dysfunction and the effects were jointly mediated by insulin resistance, inflammation, oxidative stress and energy deficit.

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Somvanshi, P. R., Mellon, S. H., Flory, J. D., Abu-Amara, D., Wolkowitz, O. M., Yehuda, R., Jett, M., Marmar, C., Hood, L., Wang, K., Lee, I., Hammamieh, R., Gautam, A., Daigle, B. J., Yang, R., Doyle, F. J.. 2018-12-17. Mechanistic insights on metabolic dysfunction in PTSD: Role of glucocorticoid receptor sensitivity and energy deficit. https://doi.org/10.1101/492827

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