Mapping the network biology of metabolic response to stress in posttraumatic stress disorder and obesity

The co-occurrence of stress-induced posttraumatic stress disorder (PTSD) and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to systematically highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing (NLP) to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin (OXT), Neuropeptide-Y (NPY), and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation.