Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: role of glucocorticoid receptor sensitivity

Abstract

Posttraumatic stress disorder (PTSD) 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 show increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation, and hypersensitive hypothalamic-pituitary-adrenal (HPA) axis. To analyze whether the co-occurrence of multiple metabolic abnormalities is independent or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multiomic 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 clinical data. We combined the metabolomics, neuroendocrine, clinical laboratory, 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, high-sensitivity C-reactive protein, homeostatic model assessment of insulin resistance, γ-glutamyltransferase, 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.

Modeling the Influence of Chronic Sleep Restriction on Cortisol Circadian Rhythms, with Implications for Metabolic Disorders

“…(vi) The influences of other causes of perturbation and response of the HPA axis (e.g., stress and posture) should be added to the model. (vii) The mathematical model presented in this work can be expanded to explicitly account for the influence of cortisol on the dynamics of metabolic mediators such as glucose and insulin as has been shown by others [ 57 , 60 , 61 , 62 , 63 ]. Such extensions would enable further investigation of the interplay among timing of meals, sleep cycles, and light exposure, which are often perturbed together for extended periods in chronic shift workers.…”

“…It should be noted that cortisol exhibits prominent pulsatile ultradian rhythms, which are not captured by the dynamics of our model. Nevertheless, previously published models of the HPA axis based on a similar framework that have primarily studied the circadian dynamics of this system have yielded insightful physiologically findings in understanding the mechanisms contributing to disruption in cortisol circadian rhythms in PTSD and depression [ 60 , 63 , 75 ].…”

Neurophysiology and Psychopathology Underlying PTSD and Recent Insights into the PTSD Therapies—A Comprehensive Review

“…A few other research studies reported that rats exposed to imminent shock have elevated p11 levels in prefrontal cortex. This study also reported that the synthetic glucocorticoid dexamethasone enhanced p11 expression through glucocorticoid response elements (GREs) in the p11 promoter, which has implications in psychopathology during PTSD [ 66 ]. Thus, the p11 protein plays a significant role in mood regulation during PTSD, and it is essential to develop novel therapeutic modalities to modulate the function of p11 in PTSD patients comorbid with major depressive disorder [ 65 ].…”

“…For example, macrophages accumulate inside adipose tissue during obesity/insulin resistance generating cytokines and adipokines that may lead to inflammation [ 72 ]. Hyperinsulinemia sensitizes adipose tissue to lipid synthesis, which is associated with increased activity of glucocorticoids [ 66 ].…”

“…Neuroendocrine disturbances in the hypothalamus-pituitary-adrenal axis (HPA) could contribute to the psychopathology of PTSD [ 78 ] ( Figure 1 ). The metabolic phenotype of PTSD may be caused partially by glucocorticoid hypersensitivity, which may affect inflammation, insulin resistance, oxidative stress, and energy deficiency [ 79 ]. PTSD patients have suppressed HPA axis activity, which progressively leads to increased catecholamine levels, corticotropin-releasing factor (CRF), and reduced cortisol levels [ 45 , 47 , 80 ].…”