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Am J Physiol Endocrinol Metab. 2019 Jul 19. doi: 10.1152/ajpendo.00065.2019. [Epub ahead of print]

Mechanistic inferences on metabolic dysfunction in PTSD from an integrated model and multi-omic analysis: Role of glucocorticoid receptor sensitivity.

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Harvard John Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, United States.
Department of Psychiatry, James J. Peters VA Medical Center, Bronx, NY. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY, United States.
Department of Psychiatry, New York Langone Medical School, New York, NY, United States.
The names of additional members of the PTSD systems biology consortium are listed in the acknowledgement section, United States.
Department of Psychiatry, University of California, San Francisco, United States.
Integrative Systems Biology, US Army Medical Research and Materiel Command, USACEHR, Fort Detrick, Frederick, MD, United States.
Institute for Systems Biology, Seattle, WA, United States.


Post-traumatic stress disorder is associated with neuroendocrine alterations and metabolic abnormalities; however, how metabolism is affected by neuroendocrine disturbances is unclear. The data from combat exposed veterans with PTSD shows increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation and hypersensitive HPA-axis. To analyze whether the co-occurrence of multiple metabolic abnormalities are independent, or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multi-omic analysis. The models for hepatic metabolism, HPA axis, inflammation and regulatory signaling were integrated to perform metabolic control analysis (MCA) with respect to the observations from our data. 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. MCA revealed mechanistic association of the HPA-axis and inflammation with metabolic dysfunction consistent with PTSD. This was supported by the data using correlational and causal analysis that revealed significant associations between cortisol suppression, hs-CRP, HOMAIR, GGT, hypoxanthine and several metabolites. Causal mediation analysis indicates that the effects of enhanced glucocorticoid receptor sensitivity (GRS) on glycolytic pathway, gluconeogenic and branched chain amino acids, triglycerides and hepatic function are jointly mediated by inflammation, insulin resistance, oxidative stress and energy deficit. Our analysis suggests that the interventions to normalize GRS and inflammation may help to manage features of metabolic dysfunction in PTSD.


HPA-axis; Neuroendocrine; PTSD; glucocorticoid signaling; mathematical modeling


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