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U.S. Department of Agriculture Western Human Nutrition Research Center Department of Nutrition University of California, Davis Davis, California 95616
Address all correspondence and requests for reprints to: Kevin D. Laugero, Ph.D., U.S. Department of Agriculture Western Human Nutrition Research Center, Department of Nutrition, University of California, Davis, Davis, California 95616. E-mail: kevin.laugero{at}ars.usda.gov.
Chronic psychological stress has profound effects on human health and well-being, and it is generally accepted that psychological stress is a burgeoning public health problem in modern-day life. However, models used to describe or predict stress-related disease are generally plagued by the paucity of information that characterizes individuals with stress, and this situation is particularly true for metabolic systems change. Given the relationship between psychological stress and many health problems that afflict modern societies, such as major depression, obesity, type 2 diabetes, and the metabolic syndrome, it seems critical to obtain greater clarity about the factors that predict and determine stress sequelae and stress-related disease.
The concept that repeated psychological stress is energetically taxing and, therefore, places the individual at greater risk of developing metabolic and behavioral disease is not new (1, 2, 3). However, at best, we have a foggy view of the energetic processes and metabolic system adaptations that actually determine this conceptual path from stress to disease. New research findings suggest a metabolic-brain feedback system that might help to explain this conceptual model of stress disease (Fig. 1
). In this dynamic chronic stress model, changes in energy metabolism and balance or reserve provide important input to brain systems [corticotropin-releasing-factor (CRF) and norepineprhine (NE)] that control activity in the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and potentially neural processes that mediate reward, emotion, appetite, arousal, attention, learning, and memory (4, 5). Although acute stress (not represented in Fig. 1) is catabolic, only when energy reserves are sufficiently taxed is there disinhibition of the metabolic-brain feedback system, thereby leading to exaggerated neuroendocrine, autonomic, and behavioral changes typical of individuals experiencing repeated episodes of stress. These exaggerated responses may increase vulnerability to disease. During chronic stress, heightened activity in CRF and NE is likely sustained by increased input from glucocorticoids (positive feedback) in parallel with and/or as a consequence of disinhibition of metabolic feedback. Note that this model accommodates food intake, which is important because, in some persons, chronic stress amplifies the drive for high-energy foods (comfort foods) (see Ref. 6). Intake of these foods is expected to prevent significant energy loss, maintain greater activity in the metabolic-brain feedback system, and damp or switch off the stress response (see Ref. 4). Moreover, the combination of increased glucocorticoid plus palatable food ingestion amplifies storage of calories into abdominal fat. Importantly, variation in the energetic response to stress may, therefore, predict and determine the ultimate fate of chronic stress in an individual, including whether or not to eat, become depressed or anxious, turn to drugs, etc. in response to repeated psychological stress.
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The impact of psychological stress on energy metabolism is evident by the gross changes in energy metabolism that accompany conditions commonly associated with chronic psychological stress (e.g. visceral obesity, body weight gain, and body weight loss). Several studies also reveal changes in energy, carbohydrate, lipid, and protein metabolism in response to psychological stress, but broad-scale and integrative metabolic system assessment in the context of psychological stress is rare (7). Whether stress-induced changes in metabolism vary from individual to individual, and how and to what degree the web of metabolic system change is fabricated and manifested under chronic psychological stress, have been given little attention. Much basic work is needed to expose the interrelationships between chronic psychological stress and broad-scale metabolic system change.
In this issue of Endocrinology, Depke et al. (8) use liver metabolic gene profiling in the mouse to characterize broad shifts in energy metabolism that result from acute and repeated psychological stress. Their findings highlight an important adaptive shift in metabolic function from acute to repeated stress and yield a deeper insight into the metabolic processes that potentially lead to energy loss and vulnerability to disease. Moreover, their findings, which expose potentially important details of stress-related metabolic networks, may provide greater insight into the processes that characterize chronic stress and potentially mediate stress system activity and adaptation (refer to Fig. 1
). A hallmark of individuals undergoing chronic stress is heightened behavioral and hypothalamic-pituitary-adrenal axis activity; the study by Depke et al. (8) suggests another potentially significant marker of chronic psychological stress and chronic stress disease: hypercatabolic activity.
In combination with traditional approaches, modern methodological tools should allow for greater metabolic profiling of psychological stress. Teague et al. (7) recently applied metabolomic approaches, using nuclear magnetic resonance spectroscopy, to show metabolic differences between acute and chronically stressed rats. As neurobehavioral circuits have been built to understand the underpinnings of chronic psychological stress, new technologies are now becoming available that can help define metabolic circuits that characterize psychological stress and possibly stress resilience, coping strategies, and disease propensity (9). Because many metabolic and behavioral diseases present together in the same individual, research geared toward clarifying the picture of metabolic system change in the context of psychological stress or neurobehavior may have profound clinical implications.
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Footnotes |
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Abbreviations: CRF, Corticotropin-releasing factor; NE, norepinephrine.
Received March 10, 2008.
Accepted for publication March 19, 2008.
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, Normal; 
, elevated; GC, glucocorticoids; SNS, sympathetic nervous system.