Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases II

Systemic disease sequelae in chronic inflammatory diseases and chronic psychological stress: comparison and pathophysiological model Rainer H. Straub Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany Address for correspondence: Dr. Rainer H. Straub, Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, BIOPARK 1, Josef-Engert-Straße 9, 93053 Regensburg, Germany. [email protected]

In chronic inflammatory diseases (CIDs), the neuroendocrine–immune crosstalk is important to allocate energy-rich substrates to the activated immune system. Since the immune system can request energy-rich substrates independent of the rest of the body, I refer to it as the “selfish immune system,” an expression that was taken from the theory of the “selfish brain,” giving the brain a similar position. In CIDs, the theory predicts the appearance of long-term disease sequelae, such as metabolic syndrome. Since long-standing energy requirements of the immune system determine disease sequelae, the question arose as to whether chronic psychological stress due to chronic activation of the brain causes similar sequelae. Indeed, there are many similarities; however, there are also differences. A major difference is the behavior of body weight (constant in CIDs versus loss or gain in stress). To explain this discrepancy, a new pathophysiological theory is presented that places inflammation and stress axes in the middle. Keywords: chronic inflammatory disease; rheumatoid arthritis; psychological stress; systemic disease sequelae

Introduction Chronic inflammatory diseases (CIDs) are accompanied by a multitude of systemic disease sequelae that are not induced by autoimmunity itself. This means that recognition of autoimmune targets by T cells or B cells is not responsible for the observed phenomena (e.g., autoantibodies do not play a direct role). In contrast, disease sequelae are a consequence of chronic alterations of bodily energy and volume regulations.1–3 The chronic inflammatory process in CIDs involves the two major stress axes: the hypothalamic–pituitary– adrenal (HPA) axis and the sympathetic nervous system (SNS). These two stress axes induce a catabolic state and activate water retention (volume expansion).1,3 Since chronic activation of stress axes in the context of CIDs has not been positively selected during the evolution of mammals,1,3,4 longterm application of this program in chronic inflammation leads to a variety of disease sequelae

(Table 1). These concepts of evolutionary medicine and neuroendocrine–immune crosstalk have been previously elucidated.1,3,4 As in CIDs, since chronic psychological stress is often linked to activation of the SNS and the HPA axis, similar disease sequelae may manifest over the long term. A direct comparison of CIDs and chronic psychological stress is discussed in this article. While rheumatoid arthritis is prototypic for CIDs, chronic psychological stress can be observed as stress stemming from job strain, posttraumatic stress disorder (PTSD), major depression, or serving as a caregiver for an Alzheimer’s disease patient. On the basis of this comparison, a pathophysiological model is presented that discusses weight gain/loss in CIDs and chronic psychological stress. Does stress induce inflammation? While in CIDs the driving force of misguided energy and volume regulation can be found in continuous inflammation of various intensities

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Table 1. Sequelae of chronic inflammatory diseases in light of altered energy regulation

Disease sequelae Depressive symptoms/fatigue Anorexia Malnutritiona Muscle wasting—cachexia

Cachectic obesity Insulin (IGF-1) resistance (with hyperinsulinemia)

Dyslipidemiab

Increased adipose tissue in the proximity of inflammatory lesions Alterations of steroid hormone axes

Elevated sympathetic tone and local sympathetic nerve fiber loss Hypertension Decreased parasympathetic tone Inflammation-related anemia

Osteopenia

Pathophysiological elements in chronic inflammation leading to energy allocation to an activated immune system Cytokine-driven (e.g., IL-1␤) sickness behavior and fatigue that increase time at rest (muscles and brain in an inactive state) Sickness behavior—related anorexia spares energy usually needed for foraging Consequence of anorexia and sickness behavior Protein breakdown in muscles is increased—amino acids used in gluconeogenesis. Cortisol-to-androgen preponderance in chronic inflammation is catabolic and inhibitory for energy-consuming courtship behavior and reproduction Protein breakdown in muscles > fat breakdown (the starvation program) Cytokine-induced (e.g., TNF-␣) insulin signaling defects in liver, muscle, and fat tissue but not in immune cells. Immune cells need insulin so that high insulin levels support the activity of the immune system (similar for IGF-1). Energy not stored in fat tissue Cytokine-driven acute phase reaction of lipid metabolism leading to higher delivery of cholesterol and other lipids to macrophages (stop of the reverse cholesterol transport with proinflammatory HDLb ) Presence of adipose tissue surrounding lymph nodes and in the proximity of inflammatory lesions reflects local store of energy-rich fuels (perhaps by local estrogens). Adipokines play a proinflammatory role Cytokine/leptin-driven hypoandrogenemia supports muscle breakdown and protein delivery for gluconeogenesis and support of an activated immune system. Cortisol-to-androgen preponderance in chronic inflammation is catabolic and antireproductive Cytokine-driven increase of SNS activity increases gluconeogenesis and lipolysis. The parallel loss of sympathetic nerve fibers in inflamed tissue supports local inflammation.73 It also stimulates lipolysis in the surrounding adipose tissue because sympathetic nerve fibers are increased there74 Cytokine-driven activation of the water retention system due to systemic water loss during inflammation Cytokine-driven decrease of PSNS activity, loss of anti-inflammatory activity of PSNS, supports allocation of energy-rich fuels to an activated immune system Cytokine-driven anemia is linked to reduced energy expenditure for erythropoiesis, increased time at rest, and insulin resistance (see above), all of which support energy allocation to the immune system High calcium and phosphorus are mandatory for energy-consuming immune reactions.75 Driven by cytokines and macrophage-derived PTH-related peptide during inflammation. In addition, an activated SNS and HPA axis stimulate bone resorption

Note: References that demonstrate the respective disease sequelae and the pathophysiological explanation can be found in detail in Ref. 1. a Hypovitaminosis D and other vitamins; deficiencies in zinc, iron, copper, and magnesium. b Dyslipidemia in chronic inflammation reflects low levels of HDL cholesterol and/or apolipoprotein A-I and appearance of an inflammatory HDL subfraction with increased serum amyloid A and ceruloplasmin, and small dense LDL particles. HPA axis, hypothalamic–pituitary–adrenal axis; IGF, insulin-like growth factor; IL, interleukin; PSNS, parasympathetic nervous system; PTH, parathyroid hormone; SNS, sympathetic nervous system; TNF, tumor necrosis factor.

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(cytokines directly activate stress axes and other disease sequelae; Table 1),1,3,4 it is not known whether a similar level of systemic inflammation appears in psychological stress. If a comparable inflammatory response accompanies psychological stress, changes in energy and volume regulation as observed in CIDs may also appear on the basis of stress-induced cytokine-driven stress axis activation. The inflammatory response during psychological stress was studied using different stress paradigms, one of which is psychosocial job strain stress. A recent meta-analysis of studies on job strain stress found a measurable effect on immune parameters, with an increase in inflammatory markers such as interleukin(IL)-6.5 Similarly, serum IL-6 was repeatedly reported to be elevated in Alzheimer’s disease caregivers.6,7 However, when one compares serum levels of IL-6 as measured with the same quantitative high-sensitivity enzyme-linked immunosorbent assay (ELISA), healthy subjects range between 1.0 and 2.0 pg/mL,8 caregivers show a mean value of 5.5 pg/mL,9 and subjects who report a high level of perceived hopelessness show levels of 3.0 pg/mL.10 Although significantly different from healthy controls, these IL-6 concentrations are low when compared to patients with rheumatoid arthritis, whose levels range between 40.0 pg/mL before anti-tumor necrosis factor ␣ (TNF-␣) therapy and 8.0 pg/mL after anti-TNF-␣ therapy, as measured with the same ELISA technique.11 Thus, patients with rheumatoid arthritis demonstrate 10 times higher serum levels of IL-6 compared to stressed or depressed patients. The question remains whether activation of stress axes and respective changes of energy regulation can occur with serum IL-6 levels of around 4.0 pg/mL. A seminal study demonstrated the interrelation between the dose of subcutaneously injected recombinant human IL-6 (rhIL-6), serum levels of IL-6, and an increase of energy expenditure in healthy volunteers.12 It was demonstrated that an injection of 0.1 ␮g/kg body weight (b.w.) of rhIL-6 increased serum levels of IL-6 to approximately 10–15 pg/mL; 1.0 ␮g/kg b.w. of rhIL-6 led to 45 pg/mL; 3.0 ␮g stimulated a serum level of 250 pg/mL; and 10 ␮g/kg b.w. was accompanied by an IL-6 serum concentration of more than 1000 pg/mL. In parallel, the maximal increase of metabolic rate as a percentage of the basal metabolic rate was 4%, 7.5%, 18%, and

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25%, respectively.12 This means that a visible influence on energy regulation was observed already at a serum level of 10–15 pg/mL, but the effect was small in these healthy volunteers. In contrast, serum levels of 45 pg/mL were related to an increase in metabolic rate of 7.5%, which would amount to approximately 600 kJ/d in a normal-sized healthy subject (basal metabolic rate: 8000 kJ/d). Such a number can be relevant in untreated patients with rheumatoid arthritis who really demonstrate these high levels of inflammation. Form this point of view, it is questionable whether increased inflammation in chronic psychological stress can lead to substantial changes in energy regulation under considerations of mild stressinduced immune system activation. Nevertheless, it was reported that not only was serum IL-6 increased under stressful situations, but so too were other cytokines, such as TNF-␣, interferon-␥ , IL-2, and others. Each cytokine might have an independent influence on stress system activation, so that additive or even synergistic cytokine effects on energy and volume regulation can exist. This might be demonstrated by endotoxin injection where several cytokines are upregulated in parallel. Indeed, endotoxin injection, which stimulates many proinflammatory cytokines (but also has direct effects via Toll-like receptor 4), increased energy expenditure by 25–40%.13 This study, using a bioassay for IL-6 levels, found that the endotoxin-induced IL-6 increase was 10 times the baseline value, which can be transferred to an increase from 1.5 pg/mL (serum level in healthy subjects8 ) to 15 pg/mL when using the modern high-sensitivity ELISA technique discussed above. Since energy expenditure rises by 4% (IL-6 at 10–15 pg/mL) with subcutaneous rhIL6 alone12 and by 25–40% with endotoxin,13 a parallel increase of different cytokine pathways—not only IL-6—seems to lead to higher energy expenditure compared to a single cytokine injection. However, this logic remains speculative as long as we do not neutralize cytokines during psychological stress while measuring energy expenditure in parallel. However, I argue in favor of another mechanism that induces a more direct effect on energy expenditure in chronic stress states independent of stressinduced peripheral inflammation: an increase in cytokines during stress might be an additional supportive pathway.

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Does psychological stress need energy? There are several ways to study increased energy expenditure in subjects with or without stress, one of which involves the consideration of wakefulness (day stress) compared to sleep. Sleep protects energy stores by approximately 25–30%, as demonstrated in excellent studies with indirect calorimetry in humans.14,15 Thus, removal of the stress of wakefulness (plus physical activity) already influences the basal metabolic rate in a strong way. Importantly, during sleep, it is mainly the brain that reduces glucose consumption by 25–30%.16 Another stress paradigm is cold stress, which also increases energy expenditure.17 In a more direct study, glucose uptake in particular regions of the brain was measured under experimental shortterm stress,18,19 demonstrating that the brain forces a stress response in order to demand glucose (and possibly also ketone bodies). On the level of the entire body, the additional intake of glucose was measured after experimental acute stress in humans (Trier Social Stress Test). This was done in the form of stress-induced intake of food served ad libitum from a rich buffet.20 The stress test lasted for only 10 min, but additional intake of glucose was 34 g, representing 571 kJ.20 The additional intake of 571 kJ amounts to approximately 25% of the daily glucose requirements of the brain (2200 kJ/d). Thus, a short-lived stressful psychological event directly allocates large amounts of energy-rich substrates to the activated brain. These stress-related changes are accompanied by typical activation of the SNS and the HPA axis, as demonstrated in many similar psychological studies.20,21 The activation of stress axes releases energy-rich substrates from stores (fat tissue, muscle) to induce gluconeogenesis and ketone body formation in the liver, in order to provide the necessary substrates to the brain. Since this is a direct influence of the brain on the rest of the body, Achim Peters referred to it very pointedly as “the brain pull” in his theory of the “selfish brain.”2,22 The brain pull is mainly mediated by activation of the HPA axis and the SNS (with the help of, for example, growth hormone and thyroid hormone), and it contrasts with the “body pull” where inhibition of stress axes and high insulin levels lead to storage of energy-rich fuels (Fig. 1).

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Figure 1. Allocation of energy-rich fuels to the brain and body. Activation of the stress axes, the hypothalamic–pituitary– adrenal (HPA) axis and the sympathetic nervous system (SNS), release free fatty acids, glycerol, and muscle amino acids to support liver gluconeogenesis and ketone body generation (energyrich substrates to the brain). Activation of the brain pull by the brain is an active program to reallocate energy-rich substrates from stores to the brain. This stress axes–driven reaction can happen under noninflamed conditions without an activated immune system. During chronic stressful states with a normally functioning, albeit mildly activated, immune system, the brain dictates to the rest of the body to reallocate energy-rich substrates to the central nervous system (the selfish brain, according to Peters2 ). The theory states that if the brain pull is not working well (defects in stress axes?), the body pull leads to excessive storage of energy-rich fuels.

To my knowledge, Achim Peters did not include the immune system, which can independently demand energy-rich fuels so that one might call it the “selfish immune system” (Fig. 1). Independence of the brain and immune system are of outstanding importance because an immediate reaction of either system is mandatory for survival. The immune system does not ask the brain whether to start an immediate reaction against an invading microbe, nor does the brain ask the immune system to escape from a lion attack. In conclusion, psychological stress forces a braindriven direct activation of stress axes. In these stressful events, the brain does not need an indirect activation of the immune system in order to demand energy-rich substrates. In contrast, the brain would not function well in stressful episodes when activation of the immune system is too strong (sickness behavior leads to increased rest). Under acute stressful psychological events, a mild peripheral immune activation may supportively serve the reallocation program. However, it is very clear that during psychological stress, the brain, similar to the immune system in CIDs, activates the same stress axes in order to release energy-rich fuels from stores, such

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as fat tissue and muscle stores. Thus, chronic activation of these stress axes might lead to similar long-standing disease sequelae. Do similar disease sequelae occur during chronic psychological stress compared with CIDs? Many disease sequelae are similar in chronic psychological stress, as substantiated in chronic job stress, PTSD, and major depression (Table 2).23–29 The clearest evidence for similar disease sequelae stems from PTSD and major depressive disorders, which might have the strongest and longest impact on energy and volume regulation. One important difference between CIDs and chronic psychological stress is not mentioned in Table 2 and relates to the phenomenon of obesity with a high body mass index above 30 kg/m2 . Obesity is an important covariate because it is associated with many similar disease sequelae on its own. While obesity with high body mass index is rare in CIDs, cachexia—characterized by sarcopenia and an increase of adipose tissue relative to lean

mass—is typical.30–32 But what about obesity in chronic psychological stress? In chronic psychological stress, one observes changes in eating behavior in more than 80% of chronically stressed subjects.28,33–36 Importantly, 40% of subjects gain weight and 40% lose weight. Characteristics of the two groups are demonstrated in Table 3. From the mentioned studies, we do not know much about the activity of the stress axes or even energy expenditure. Nevertheless, since the two response types are characterized by low exercise level (weight gain) versus high exercise level (weight loss), one can speculate that the weight gainers have low stress axis activity, while the weight losers show increased activity. These response types are also present in the chronic stress state of major depression.23,24 In major depression, two groups were separated: one that gains weight (atypical depression) and one that loses weight (melancholic depression).23,24 The weight losers demonstrate anorexia, a hyperaroused state and anxiety, decreased sleep, high HPA axis activity, high SNS activity, high systolic blood

Table 2. Similar disease sequelae in CIDs and chronic psychological stress23–29

Disease sequelae Depressive symptoms/fatigue Anorexia Malnutritiona Muscle wasting—cachexia Dyslipidemiab Insulin resistance (hyperinsulinemia) Alterations of steroid hormone axes Elevated sympathetic tone Hypertension, volume overload Decreased parasympathetic tone Inflammation-related anemia Osteopenia

CIDs Very prevalent Often Often Typical Often Often Activation of HPA axis stop of HPG axis Typical Often

Chronic psychological stress Very prevalent Often Often In melancholic type of depression Present in PTSD, job stress, and major depression Women > men obese > lean Typical in melancholic stress lean  obese Typical in melancholic stress lean  obese In PTSD and melancholic depression

Often

In PTSD and melancholic depression

Often Often

n.d. Present in PTSD, job stress, and major depression

a

Hypovitaminosis D and other vitamins; deficiencies in zinc, iron, copper, and magnesium. Dyslipidemia reflects low levels of HDL cholesterol and/or apolipoprotein A-I and appearance of an “inflammatory HDL subfraction” with increased serum amyloid A and ceruloplasmin and small dense LDL particles. HPA axis, hypothalamic–pituitary–adrenal axis; HPG, hypothalamic–pituitary–gonadal axis; IGF, insulin-like growth factor; n.d., not well-determined; PSNS, parasympathetic nervous system; PTSD, posttraumatic stress disorder; SNS, sympathetic nervous system. b

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Table 3. Characteristics of chronically stressed subjects gaining/losing weight

40% gain weight

40% lose weight

Upper range of normal weight at the beginning of prospective studies Lower education level Low social work support Less vegetable and fruit consumption Low fiber intake More alcohol (men) No exercise Low levels of satisfaction (women) High scores in neuroticism (women) Increase of palatable food intake (snacks with high fat/high sugar)

Normal or underweight at the beginning of prospective studies Higher education level High social work support High vegetable consumption High fiber intake No alcohol (men) High exercise level (2 h/week of vigorous exercise) High level of extroversion (men)

pressure, diminished libido (low hypothalamic– pituitary—gonadal axis activity), sarcopenia, insulin resistance and increased visceral fat, dyslipidemia, osteoporosis, and low-grade smoldering inflammation. The second group of atypically depressed patients demonstrate increased food intake and consist of more women than men, and fewer smokers than nonsmokers; they show an apathetic or hypoaroused state, hypersomina, diminished libido, low HPA axis and SNS activity, and low systolic blood pressure, but also insulin resistance and increased visceral fat, dyslipidemia, normal bone, and a higher degree of smoldering inflammation. From these studies in psychological stress and major depression, two response types seem to be present. There are certainly intermediate states between the two extremes, but the extremes can teach us some principles. The question arises whether the two response types depend on the inflammatory state.

decline, which was called the ACTH–cortisol dissociation, also observed in acutely inflamed patients.41 In CIDs, we observed a chronically inadequate response of the HPA axis in relation to inflammation, which we and others called HPA axis deficit or disproportion principle.42,43 In CIDs, it was proposed that the HPA axis response is low due to the chronic inhibitory influence of circulating proinflammatory cytokines, particularly the proinflammatory TNF-␣.44 Another explanation for an inadequate HPA axis response was recently discussed by Edwards.45 In his presentation, inflammation-derived proinflammatory cytokines stimulate liver 11␤-hydroxysteroid dehydrogenase type 1 so that cortisol production from circulating cortisone becomes markedly increased. These elevated serum cortisol levels inhibit the HPA axis via negative feedback. A third theory placed IL-6–stimulated cortisol production from the adrenal gland in the middle, so that it becomes independent of ACTH.46 All theories are attractive, and they are not mutually exclusive, given that inflammation plays a key role for the HPA axis deficit either as a direct cytokine effect on the hypothalamus, pituitary gland, or adrenal glands or an indirect effect via the liver and 11␤-hydroxysteroid dehydrogenase type 1. In summary, a cytokinedriven alteration leads to inadequate secretion of HPA axis hormones. In parallel, the activity of the SNS is increased to compensate for the lack of HPA axis activity, a phenomenon that has been demonstrated in CIDs.43 In addition, since the HPA axis and SNS are

From CIDs, we learned the important concept of stress axis activation and dissociation Under short-lived inflammatory conditions (e.g., after injection of IL-6, interferon-␣, or interferon-␥ to human subjects), a strong response of the stress axes can be observed.12,23,24,37–40 Both the HPA axis and the SNS are stimulated in parallel. This immediate response is not of long duration (a few days).37,40 Particularly, the adrenocorticotropic hormone (ACTH) response was shown to

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cooperative in many instances,47–54 the relative deficiency of one system might also change the efficiency of the other, still active system (as in the cases of, for example, glucose regulation, blood pressure stabilization, bronchial lumen diameter, and hypotension in sepsis). Thus, inflammation can largely change the activity of the stress axes and possibly also their cooperative efficiency, leading to activation but also dissociation of the HPA axis and the SNS.55,56 The model: inflammation determines the brain pull and body pull and, thus, the weight response in CIDs and chronic psychological stress The new model: CIDs in focus I hypothesize that inflammation is the critical determinant for changes of the brain pull and body pull. High inflammation inhibits the brain pull, as demonstrated above for CIDs, because of the activation and dissociation of stress axes. However, CID patients do not become obese or even lose weight because the immune system is using energy-rich fuels to a large extent. Importantly, in CIDs, a high body mass index is positively associated with a better disease course and cardiovascular outcome.57–60 This is most probably a sign of milder inflammation in CIDs leading to a smaller inflammatory load. This is summarized in Figure 2A. The new model: psychological stress with normal weight or weight loss When psychological stress begins, the starting conditions—whether obese or lean, inflammatory or noninflammatory, strong or weak stress axis responsiveness (see next section), or high or low muscle mass—are of outstanding importance. When psychological stress arises in people with little peripheral inflammation, little obesity, and high stress axis activity, the brain pull is strong while the immune system does not need much energy. The consequence is normal weight or weight loss (Fig. 2B). The new model: psychological stress with weight gain However, when psychological stress begins in people with increased peripheral inflammation, high body weight, and generally low stress axis activity, it seems to lead to a positive vicious spiral that increases both peripheral inflammation and weight. This is due to inflammation-induced inhibition of the brain pull and activation of the body

Figure 2. Change of the brain pull by an activated immune system or by an activated brain. (A) Inhibition of the brain pull and increased energy expenditure of the immune system in chronic inflammatory diseases (CIDs). When the immune system is activated as in CIDs or during acute-lived inflammation (e.g., severe energy-consuming infection), the selfish immune system stops the activity of the selfish brain (sickness behavior), changes the two stress axes, induces insulin resistance plus hyperinsulinemia, and dictates to the rest of the body to reallocate energy-rich substrates to activated immune cells (the selfish immune system). This leads to weight loss or cachectic obesity in CIDs. (B) Activation of the brain pull in a situation of psychological stress but without peripheral inflammation. Now the brain dictates to the rest of the body to reallocate energy-rich substrates to the brain. This is mediated by the perfectly functioning stress axes in the absence of hyperinsulinemia and inflammation, and leads to weight loss. HPA, hypothalamic–pituitary–adrenal axis; SNS, sympathetic nervous system.

pull (Fig. 3A). The situation increasingly resembles the situation in CIDs; however, peripheral inflammation is not high enough to induce weight loss because the immune system is not fully engaged. Nevertheless, signs of inflammation, such as elevated serum levels of IL-6, are predictive of longterm outcome,61 which demonstrates that longstanding smoldering inflammation is unfavorable. The new model: a continuum Possibly, there exists a continuum between the healthy state, chronic psychological stress without peripheral inflammation, chronic

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(Fig. 3B). With increasing weight the inflammatory load gradually increases, reaching high levels of 10 pg/mL of serum IL-6. However, stress-related serum IL-6 will rarely reach the flare-up serum level of IL-6 typical for CIDs (around 40–100 pg/mL). Thus, psychological stress with high serum levels of IL-6 and weight gain will not be self-limiting via activation of energy expenditure by the immune system. The role of the programmed brain

Figure 3. Chronic psychological stress meets peripheral inflammation. (A) Inhibition of the brain pull and change of the body pull in a situation with psychological stress plus peripheral inflammation. This situation can appear when people with obesity and pre-existing peripheral inflammation start a prolonged period of psychological stress. Under these conditions, a continuum between normal weight and weight gain might exist, which is depicted in the yellow area in panel B. (B) Hypothetical model of interrelation between peripheral inflammation and energy expenditure of the brain (EEbrain) and immune system (EEis) and storage of energy in adipose tissue. The continuum largely depends on the energy expenditure of the brain and immune system. The energy expenditure of skeletal muscle is not demonstrated because it is constant in our sedentary way of life. In a range of mild smoldering inflammation (IL–6: 2–10 pg/mL, yellow area), energy expenditure by the immune system is minimal and weight gain is possible. Higher than normal storage is linked to increasing mild smoldering inflammation. In a range of increased inflammation (IL-6 above 12 pg/mL), energy expenditure by the immune system exponentially increases and brain energy consumption decreases, the consequence of which is normal weight or weight loss. CIDs, chronic inflammatory diseases; EE, daily energy expenditure.

psychological stress with increasing peripheral inflammation, and CIDs with different degrees of inflammatory load. Such a continuum is presented in Figure 3B. Depending on energy expenditure of the brain and the immune system, storage of energy-rich fuels is possible in adipose tissue 14

Research during the last decades in pregnant women demonstrated that stressful events, such as undernutrition, psychological stress, anxiety, psychiatric disease, and smoking, can program the brain of the fetus for his/her entire life. A well-known fact is that low birth weight or thinness at birth predicts increased risk of adult hypertension, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, death from coronary heart disease, and increased body weight.62 Importantly, long-term programming is mainly directed toward the activity of the HPA axis and the SNS.63 It seems that the third trimester is a vulnerable phase because an increase of endogenous cortisol during this period can induce long-standing exaggerated HPA axis responses with elevated cortisol levels.64–67 In contrast, PTSD in response to the September 11, 2001 attacks in New York City induced low levels of endogenous cortisol in exposed mothers but more strikingly also in their babies.68 Undernutrition during the third trimester is accompanied by obesity and glucose intolerance in children.69 These examples clearly demonstrate that our stress axes are programmed in utero for a long time. Since the two stress axes are outstandingly important in determining the brain pull, this prerequisite may largely change the outcome to chronic psychological stress with respect to weight. It also may change the situation in CIDs because animal and human studies demonstrated the favorable role of an intact HPA axis.70–72 Conclusions The starting point of the considerations in CIDs was the energy appeal reaction of an activated selfish immune system, the chronic use of which induces detrimental disease sequelae, such as metabolic syndrome (Table 1). The question arose as to whether people experiencing chronic psychological

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stress have similar disease sequelae compared to CIDs and, if so, what the reasons are. It was discussed that stress induces a mild inflammatory response, which, however, is not sufficient to explain disease sequelae. It was demonstrated that psychological stress requires substantial energy, and that chronic energy reallocation programs may induce similar long-term problems as in CIDs. Stress such as CIDs stimulate the same stress axes (HPA and SNS). Many long-term disease sequelae are similar in CIDs and chronic psychological stress. It has been shown that there is a special situation for body mass index/obesity because it appears only in a subgroup of patients with chronic psychological stress (40%). In theory, this was linked to lowered stress axis activity (low brain pull).2,22 I proposed the hypothesis that peripheral inflammation (e.g., in fat tissue) is the critical determinant for the development of obesity because inflammation—as in CIDs— inhibits the brain pull. Low-grade smoldering inflammation can lead to weight gain due to blockade of the brain pull, while strong proinflammatory conditions in CIDs keep weight constant due to blockade of the brain pull and the delivery of substrates to the activated immune system. The perspective demonstrated in this article suggests two approaches in the future: (1) one needs to improve diagnostics and preventive therapy of longterm disease sequelae in CID patients and chronically stressed people; and (2) therapeutic approaches that interfere with cellular bioenergetics and bodily energy pathways may be new targets for the treatment of CIDs and possibly also in chronic psychological stress. Conflicts of interest

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The author declares no conflicts of interest. 18.

References 1. Straub, R.H. et al. 2010. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med. 267: 543–560. 2. Peters, A. et al. 2004. The selfish brain: competition for energy resources. Neurosci. Biobehav. Rev. 28: 143–180. 3. Straub, R.H. 2012. Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J. Mol. Med. 90: 523–534. 4. Straub, R.H. & H.O. Besedovsky. 2003. Integrated evolutionary, immunological, and neuroendocrine framework for

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