Epidemiological studies implicate stress as an important factor contributing to the increasing prevalence of metabolic disorders. Studies have correlated visceral obesity and atherosclerosis with hyper-cortisolemia, a sequela of chronic psychological stress in humans and animals. Although several hormonal markers of stress have been associated with various metabolic disorders, the mechanism by which these hormones alter metabolic functions have not been established. We used an in vitro model system, culturing 3T3-L1 pre-adipocytes and RAW 264.7 macrophages in the presence or absence of cortisol, to analyze cell signaling pathways mediating changes in metabolic functions. Our analysis revealed that cortisol up-regulated the expression and function of two serotonin (S) receptors, HTR2c and HTR5a. HTR2c and HTR5a were also directly involved in mediating cortisol enhanced adipogenesis when pre-adipocytes were cultured alone or in the presence of macrophages. Finally, cortisol treatment of pre-adipocytes co-cultured with macrophages enhanced adipogenesis in both macrophages and pre-adipocytes.

Regulation of adipogenesis, the root cause for obesity, is very poorly understood. However, studies have presented evidence of immuno-metabolic regulation of adipose tissue during periods of chronic psychological stress, leading to adverse conditions related to stress manifestation, including visceral obesity and atherosclerosis. Despite pronounced association of hormonal markers of stress with dys-regulated metabolic states, the contributing signalling events are yet to be established. It is apparent that to understand contributing signalling events we need a model. Although an in vivo model is preferred, it is difficult to establish. The current report, therefore, presents an in vitro model system for the simulation of adipose tissue in a chronic stress micro-environment by growing pre-adipocytes with macrophages in the presence and absence of stress hormones. In this report, effects of cortisol and serotonin on the kinetics of immune and metabolic changes in adipocytes and macrophage (alone and co-cultured) was studied through whole genome transcriptome profiling. A transition from pro- to anti-inflammatory response in the immune profile of pre-adipocytes, with increasing time in co-culture with macrophages, was observed. This transition was reversed by stress hormones cortisol and/or serotonin.

Psychological stress perturbs normal physiological function or homeostasis. Restoration of normalcy demands more supply of energy. A physiological mechanism via activated stress response system is aimed at providing quick energy to deal with such emergency situations. If stress response system remains activated for longer period, maintaining physiological homeostasis becomes difficult because of higher demand for energy which eventually leads to increased susceptibility to infection or disease. Although there are reports, associating psychological stress with physiological functions and diseases, a clear understanding of mechanism of stress manifestation is yet to be established. In order to facilitate extensive exploration and prediction of possible mechanisms, integration of molecular (gene-level) data pertaining to psychological stress, physiological processes and stress-associated diseases is needed. We report power of text-mining in combination with our data-integration methods and mathematical formulation to develop integrated gene-association networks. These networks can be analyzed to gain holistic insights into the relationship between psychological stress-associated genes (stressome) and related physiological functions and diseases. We built the human psychostressome networks to understand and predict pathways and candidate genes responsible for perturbing balance among various physiological functions and disease manifestation. Using the current methodology, we were able to predict involvement of serotonin receptors and uridine 5'-diphospho-glucuronosyltransferases in mediating effects of psychological stress.

Stress has long been known to increase susceptibility to health disorders. In 2009, American Psychological Association further established association of stress to serious health problems. However, a quantitative and accurate way to evaluate and estimate stress status of individuals is still a big challenge. It has been shown, in large animal models using cattle, that psychological stress can be quantified as well as disease susceptibility could be predicted through biomarker discovery. Taking cue from those studies, we have evaluated and estimated psychological stress level of individuals theoretically and validated experimentally. Various biomarkers have also been identified which can be associated to psychological stress to predict stress status of unknown individuals.

Stress is perhaps easiest to conceptualize as a process which allows an organism to accommodate for the demands of its environment such that it can adapt to the prevailing set of conditions. Psychological stress is an important component with the potential to affect physiology adversely as has become evident from various studies in the area. Although these studies have established numerous effects of psychological stress on physiology, a global strategy for the correlation of these effects has yet to begin. Our comparative and systematic analysis of the published literature has unraveled certain interesting molecular mechanisms as clues to account for some of the observed effects of psychological stress on human physiology. In this study, we attempt to understand initial phase of the physiological response to psychological stress by analyzing interactions between innate immunity and metabolism at systems level by analyzing the data available in the literature. In light of our gene association-networks and enrichment analysis we have identified candidate genes and molecular systems which might have some associative role in affecting psychological stress response system or even producing some of the observed terminal effects (such as the associated physiological disorders). In addition to the already accepted role of psychological stress as a perturbation that can disrupt physiological homeostasis, we speculate that it is potentially capable of causing deviation of certain biological processes from their basal level activity after which they can return back to their basal tones once the effects of stress diminish. Based on the derived inferences of our comparative analysis, we have proposed a probabilistic mechanism for how psychological stress could affect physiology such that these adaptive deviations are sometimes not able to bounce back to their original basal tones, and thus increase physiological susceptibility to metabolic and immune imbalance.

Stress in general can be defined as a state of threatened balance, equilibrium or harmony that tends to disturb the homeostasis of the body. Stress can be of many kinds viz. psychological, physiological, social, emotional, and nutritional. Albeit the distinct kinds of stress stated in the aforementioned stress list, it is hard to bring out a clear distinction between them since each stress may precede or succeed the manifestation of any other. The studies discussed in the review elucidate effects of psychological stressors (PS) on diseases such as cancer, AIDS, epidermal abnormalities, obesity, and various inflammatory diseases like colonic inflammations, Coronary Artery Disease (CAD), Coronary Heart Disease (CHD), asthma. From these studies, further attempt was made to establish the basic mechanisms which come into play during a stressor stimulus and consequently modulate the physiology of the body. In this review we have highlighted effects of PS on diseases while simultaneously building on the modes of operation of PS to alter physiology and its further implications in developing potential psychotherapeutic methods for disease treatment.