Available online at www.sciencedirect.
com
Stress hormones: physiological stress and regulation of
metabolism
Ioannis Kyrou1 and Constantine Tsigos2
Stress, defined as a state of threatened homeostasis, mobilizes
a complex spectrum of adaptive physiologic and behavioral
responses that aim to re-establish the challenged body
homeostasis. The hypothalamic-pituitary-adrenal (HPA) axis
and the sympathetic nervous system (SNS) constitute the main
effector pathways of the stress system, mediating its adaptive
functions. In western societies, indices of stress correlate with
increasing rates of both obesity and metabolic syndrome which
have reached epidemic proportions. Recent data indicate that
chronic stress, associated with mild hypercortisolemia and
prolonged SNS activation, favors accumulation of visceral fat
and contributes to the clinical presentation of visceral obesity,
type 2 diabetes, and related cardiometabolic complications.
Reciprocally, obesity promotes a systemic low-grade
inflammation state, mediated by increased adipokine
secretion, which can chronically stimulate the stress system.
Addresses
1
WISDEM, University Hospital Coventry and Warwickshire, Clinical
Sciences Research Institute, Warwick Medical School, University of
Warwick, Coventry CV2 2DX, UK
2
YGEIA Hospital Athens, 82 Vas. Sophias Avenue, Marousi 151 23, 115
28 Athens, Greece
Corresponding author: Kyrou, Ioannis (I.Kyrou@warwick.ac.uk) and
Tsigos, Constantine (ctsigos@gmail.com)
Current Opinion in Pharmacology 2009, 9:787–793
This review comes from a themed issue on
Endocrine and metabolic diseases
Edited by Klaus Seedorf and Pascal Ferré
Available online 14th September 2009
1471-4892/$ – see front matter
# 2009 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coph.2009.08.007
Introduction
The adaptive response to acute stress is critical for the
survival of the individual. Prolongation of this response,
however, as in chronic stress, can have detrimental effects
on whole body metabolism and, especially, on glucose
homeostasis [1]. Glucocorticoids and catecholamines,
the principal hormonal effectors of the stress system,
appear to mediate these effects over time, progressively
leading to various manifestations of the metabolic syn-
drome. Growing evidence suggests a significant positive
association between increased cortisol levels, weight gain
and enhanced secretion of proinflammatory hormones
and cytokines (adipokines) by adipose tissue depots.
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Thus, chronic hypercortisolemia may contribute to vis-
ceral fat accumulation and insulin resistance, while cir-
culating adipokines can activate the acute phase reaction
and may act as a chronic stimulus to HPA axis, thus,
forming a deleterious vicious cycle [2].
This review briefly describes the stress system, highlights
potential mechanisms leading to stress-related cardiome-
tabolic disease and discusses available clinical data which
link chronic stress to the development of type 2 diabetes.
Defining stress and the normal stress
response
Stress is defined as a state of threatened homeostasis,
following exposure to extrinsic or intrinsic adverse forces
(stressors) [3]. In order to re-establish the disturbed equi-
librium against an imposed stressor, a repertoire of
physiologic and behavioral responses is rapidly mobilized,
constituting the adaptive stress response. In this context,
attention is enhanced and brain functions focus primarily
on the perceived threat. Somatically, cardiac output and
respiration are accelerated, catabolism is increased and
blood flow is redirected to temporarily provide higher
perfusion to threatened sites and to the aroused brain,
heart, and muscles. These responses are normally tran-
sient and aim to maximize the chances of the individual
for survival. However, when chronically stimulated, the
adaptive stress response may turn maladaptive with
potentially harmful consequences [4]. Indeed, excessive
and/or chronically imposed stressors can impair a number
of essential physiologic functions, such as metabolism,
growth, reproduction, and immunocompetence, as well as
personality development and behavior. It is of note,
however, that the ability of each individual to respond
to various stressors is determined by a combination of
genetic, developmental, and environmental factors which
affect the outcome of adaptive responses and, thus,
dictate, at least to a degree, the susceptibility to chronic
stress [5].
Central control stations and effector
pathways of the stress system
The stress system is subserved by a complex neuroendo-
crine, cellular and molecular infrastructure, extending
in the central nervous system and the periphery. The
central control stations of this system are positioned
strategically in the hypothalamus and the brain stem
and primarily include the parvocellular corticotropin-
releasing hormone (CRH) and arginine–vasopressin
neurons of the paraventricular nuclei of the hypothalamus
Current Opinion in Pharmacology 2009, 9:787–793
788 Endocrine and metabolic diseases
Figure 1
Simplified schematic representation of the stress system, its central
control stations and its effector pathways. PVN: paraventricular nucleus,
LC: locus coeruleus, CRH: corticotropin-releasing hormone, ACTH:
adrenocorticotropic hormone. Activation is represented by solid lines
and inhibition by dashed lines.
and the locus coeruleus–norerpinephrine system (central
sympathetic system) (Figure 1) [3].
The hypothalamus regulates the anterior pituitary
secretion of ACTH, mainly via CRH, while arginine–
vasopressin (AVP) contributes synergistically [6,7]. CRH
Table 1
Selected glucocorticoid sensitive genes involved in important metabolic pathways
Upregulated genes — Pathway affected
Leptin — Energy homeostasis
GLUT4 — Glucose trasnport
Glucose-6-phosphatase — Gluconeogenesis
Hepatic PEPCK — Gluconeogenesis
Lipoprotein lipase — Lipid metabolism
Hormone sensitive lipase — Lipolysis
VLDL receptor — Lipoprotein metabolism
Tyrosine aminotransferase — Amino acid catabolism
Tryptophan oxygenase — Amino acid catabolism
GLUT4: Glucose transporter 4; PEPCK: Phoshpoenolpyruvate carboxykinase; VLDL: Very low-density lipoprotein; CRH: Corticotropin-releasing
hormone; HPA: Hypothalamic-pituitary-adrenal; POMC: Proopiomelanocortin; TNF-a: Tumor necrosis factor-a.
Current Opinion in Pharmacology 2009, 9:787–793
and AVP are both secreted into the portal system in a
synchronized mode, characterized by a precise circadian
rhythm, exhibiting increased secretory pulses during the
early morning hours that precede ACTH and cortisol
secretory bursts in the general circulation [8]. This diurnal
rhythm can be markedly disrupted by imposed stressors [9].
In turn, circulating ACTH stimulates the adrenal cortex to
secrete glucocorticoids (Figure 1), which are the final
mediators of the HPA axis and play a crucial role in
mounting the adaptive response to stress. Glucocorticoids,
via their wide-spread glucocorticoid receptors, act on
positive or negative glucocorticoid responsive elements
(GREs) to activate or repress, respectively, a plethora of
genes, many of which are directly or indirectly implicated
in vital metabolic pathways. Thus, cortisol appears to
upregulate genes encoding lipoprotein receptors and
enzymes of glucose, lipid, and amino acid metabolism,
while suppresses genes encoding CRH, proopiomelano-
cortin, adiponectin, and interleukin-6 (Table 1) [10–13].
Importantly, glucocorticoids also control the basal activity
of the HPA axis and are crucial for the appropriate termin-
ation of every stress response, by providing negative feed-
back at the hypothalamic and pituitary level, as well as at
higher brain centers (Figure 1) [14].
The sympathetic nervous system (SNS) constitutes the
other principal effector component of the stress system,
providing a mechanism which allows rapid regulation of
vital functions (e.g. cardiovascular, respiratory, gastrointes-
tinal, renal, and endocrine functions) [15,16]. Sympath-
etic innervation of peripheral organs originates from the
efferent preganglionic fibers, whose cell bodies lie in the
intermediolateral column of the spinal cord, while the SNS
also offers a humoral contribution to the stress response,
providing most of the circulating epinephrine and part of
the norepinephrine from the adrenal medulla (Figure 1).
Endocrine and metabolic complications of
chronic stress
As part of an adaptive response to stress, the activation of
both the HPA axis and the SNS is programmed to be not
Downregulated genes — Pathway affected
CRH — HPA axis regulation
POMC — HPA axis and appetite control
TNF-a — Proinflammatory response
Interleukin-6 — Proinflammatory response
Interleukin-8 — Proinflammatory response
Adiponectin — Insulin signaling, Atherogenesis
Prolactin — Reproduction
Osteocalcin — Bone metabolism
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 Physiological stress and regulation of metabolism Kyrou and Tsigos 789

only sufficient to restore homeostasis, but also of limited Figure 2

duration. From an evolutionary perspective, the ability to
self-restrain adaptive stress responses is considered
equally important for a successful outcome, so that the
associated catabolic, antireproductive, antigrowth and
immunosuppressive effects are transient and in favor of
survival [3,17]. Chronic activation of the stress system can
render these effects detrimental by prolonging their
duration.

Chronic hypercortisolemia is considered to play a critical

role in these deleterious processes. Indeed, in the context
of a mobilized stress response, glucocorticoids exert
primarily catabolic effects, recruiting all available energy
resources to defend body homeostasis against the
imposed stressor. Thus, hepatic gluconeogenesis is
enhanced, circulating glucose levels are increased and
lipolysis is induced. Additionally, protein degradation is
promoted at multiple tissues (e.g. muscle and bone) to
provide amino acids which can serve as an additional
substrate for oxidative pathways. Furthermore, glucocor-
ticoids antagonize the anabolic actions of growth and
thyroid hormones, insulin and sex steroids on their target
tissues (Figure 2) [18]. This stress-related metabolic shift
toward a generalized catabolic state typically reverses
upon retraction of the posed stressor. Prolonged and
nonremitting stress, however, via chronic hypercortisole- Schematic representation of reciprocal relations between chronic stress,
mia, can progressively cause visceral fat accumulation, increased cortisol production, and visceral obesity which may lead to
clinical manifestations of the metabolic syndrome. Chronic
decreased lean body mass, and insulin resistance [2,19–
hypothalamic-pituitary-adrenal (HPA) axis activation favors visceral
21]. The clinical consequences of chronic hypercortiso- obesity and directly stimulates adipocyte accumulation, while
lemia are also influenced significantly by the sensitivity of suppresses the beneficial effects of the gonadal and the growth
peripheral tissues to glucocorticoids, which depends on hormone axis. Following weight gain, production of IL-6, TNF-a, PAI-1
the tissue-specific concentration and activity of glucocor- and resistin is increased, while adiponectin production is reduced, thus,
contributing to amplified inflammatory load which is linked to the
ticoid receptors, on the circulating and tissue levels of development of the metabolic syndrome. Reciprocally, adipose-derived
cortisol-binding globulin (CBG), and on the local expres- IL-6 may further stimulate the HPA axis, forming a deleterious vicious
sion of 11b-hydroxysteroid dehydrogenase type 1 (11b- cycle. CRH: corticotropin-releasing hormone, ACTH:
HSD1) [22]. It is of note that, the expression of 11b- adrenocorticotropic hormone, TNF-a: tumor necrosis factor-a, IL-6:
interleukin-6, PAI-1: plasminogen activation inhibitor-1, LH: luteinizing
HSD1, an enzyme that locally catalyzes the conversion of
hormone, FSH: follicle-stimulating hormone, GH: growth hormone, IGF-
the inactive cortisone to cortisol, is enhanced in adipose 1: insulin-like growth factor-1. Stimulatory effects are represented by
tissue depots of obese individuals, potentially promoting solid lines and inhibitory effects by dashed lines.
the development of central obesity and metabolic syn-
drome [23,24].

Chronic stress is also characterized by increased sym-
pathoadrenal system activity, which can contribute to
impaired glucose tolerance and to increased risk for
acute cardiovascular events [25,26–28]. Furthermore,
behavioral changes affecting physical activity (e.g.
sedentary lifestyle) and dietary habits (e.g. increased
portion size, comfort eating, and alcohol consumption)
are commonly seen in chronic stress disorders, leading
to weight gain and potentially to abnormalities of
glucose and lipid metabolism (Figure 3) [29,30]. More
recently, chronic stress has been also associated with a
low-grade inflammatory state which follows fat accumu-
lation, especially visceral, as described in the following
section.
Obesity as a state of unremitting inflammatory
stress
Obesity is now widely recognized as a chronic low-grade
inflammatory state which persists for as long as the
excessive body weight is maintained [31]. Recent evi-
dence links this unremitting inflammatory stress to the
pathogenesis of both type 2 diabetes and atherosclerosis
[32,33].
Cytokines and other humoral mediators of inflammation
are potent activators of the central stress response, form-
ing a feedback loop through which the immune/inflam-
matory system communicates with the brain [34]. IL-6 is
considered the main circulating cytokine and appears to

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790 Endocrine and metabolic diseases
Figure 3
Stress and derangement of metabolic homeostasis. Chronic stress, with
the resultant activation of both the hypothalamic-pituitary-adrenal (HPA)
axis and the sympathetic nervous system (SNS), together with significant
changes in health behaviors, can progressively contribute to the
development of visceral obesity and metabolic syndrome.
play a critical role in the immune stimulation of the HPA
axis (Figure 2) [35,36].
As with other adaptive stress responses, typical inflam-
matory responses are programmed to subside once the
initial threat is contained. Thus, at sites of conventional
inflammation (e.g. sites of local infections and injuries)
cytokines are secreted by immune cells for limited
periods in order to avoid prolonged macrophage activation
which would have destructing effects [37].
By contrast, the obesity-related inflammatory state is
characterized by failure to resolve because of a vicious
cycle between adipocytes and macrophages inside each
fat depot. As weight gain progresses, adipokines and
Current Opinion in Pharmacology 2009, 9:787–793
chemokines are steadily secreted from adipocytes into
the systemic circulation, chemoattracting and recruiting
mononuclear cells from the bloodstream into the expand-
ing adipose tissue, thus, forming a growing population of
resident macrophages [38]. In turn, these macrophages
release locally cytokines (e.g. TNF-a and IL-6) which
further stimulate the secretion of proinflammatory adi-
pokines, suppress the expression of adiponectin and
promote insulin resistance in adipocytes [39]. Progress-
ively this process results in a chronic, low-grade inflam-
mation with increased release of adipokines and
cytokines into the circulation, which exert adverse meta-
bolic effects on various tissues and organs (e.g. endo-
thelium, liver, and muscles) [31]. Thus, obese patients
typically exhibit increased levels of proinflammatory adi-
pokines in the circulation (e.g. leptin, resistin, IL-6, and
TNF-a) that strongly correlate to the manifestations of
the metabolic syndrome [40]. Notably, elevated levels of
CRP and IL-6 are strongly associated with increased risk
of type 2 diabetes [41]. Furthermore, other common
markers of inflammation (e.g. haptoglobin, fibrinogen,
and sialic acid) have also been associated prospectively
with the development of diabetes in adults, while chronic
subclinical inflammation relates independently to insulin
resistance even in nondiabetic subjects. Conversely,
plasma adiponectin, a unique anti-inflammatory adipo-
kine, exhibits an inverse correlation with cardiometabolic
complications [42]. Interestingly, thiazolidinediones, a
class of insulin sensitizers, exert also anti-inflammatory
and antiatherogenic properties, reducing CRP and TNF-
a levels, while statins decrease the risk of diabetes, at
least partly, because of their anti-inflammatory effects
[43].
Clinical data linking chronic stress,
depression and type 2 diabetes
It has been long suspected that a bi-directional relation-
ship exists between diabetes and chronic stress disorders,
such as depression. Melancholic depression provides the
prototypic example of chronic hyperactivation of the
stress system which can result in damaging somatic
effects [1]. An increasing volume of evidence is now
indicating that patients with depression may develop
manifestations of the metabolic syndrome (e.g. visceral
obesity, hypertension, dyslipidemia, and impaired glu-
cose tolerance), atherosclerosis and osteopenia, as well as
certain infectious and neoplastic diseases [2,44]. Notably,
when these patients are left untreated they exhibit a
significantly compromised life expectancy (reduced by
15–20 years after excluding suicides) [18].
Several studies have demonstrated that being depressed
at baseline increases the risk of subsequently developing
type 2 diabetes and that this association is not explained
by other known diabetes risk factors, including obesity,
family history of type 2 diabetes, activity level, smoking,
and alcohol consumption [45–48]. Indeed, according to a
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 Physiological stress and regulation of metabolism Kyrou and Tsigos 791
recent meta-analysis which included prospective studies
of depression predicting incident type 2 diabetes, depres-
sion appears to increase the risk of type 2 diabetes by 60%
[49]. Additionally, major stressful life events may be
associated with type 2 diabetes onset. As shown in the
Hoorn Study, increased visceral fat accumulation and a
higher prevalence of previously unknown type 2 diabetes
was indeed related to a high number of relatively common
major life events during a preceding five-year period [50].
Moreover, a recent case–control retrospective study in
premenopausal women demonstrated that women with
rapid onset of weight gain after an exposure to a signifi-
cant stressful event were characterized by the develop-
ment of obesity and over-activated adrenocortical
function [51]. Other studies, in the last few years, have
also provided significant evidence that chronic work stress
predicted general and central obesity during midlife,
which was largely independent from covariates
[52,53]. Interestingly, female students in the UK that
exhibit weight gain over the first year at university have
higher levels of perceived stress [54]. Thus, growing
evidence supports that stress and depression may, in
some circumstances, precede the onset of central obesity
and type 2 diabetes, potentially participating in the
underlying pathophysiology.
On the other hand, diabetic patients exhibit depression
rates up to twice as high compared to persons without
diabetes. Data from a meta-analysis documented that
presence of diabetes nearly doubles the odds of comorbid
depression, a stable finding not affected by assessment
method, subject source, gender or type of diabetes [55].
Although clear pathogenetic links between stress and
diabetes are yet to be proven, it is interesting to note
that, effective treatment of depression in diabetic
patients appears to improve glycemic control, indepen-
dently of the differential effects of such treatment on
body weight [56]. Controlled trials of cognitive behavioral
therapy demonstrated that improvements in depression
scores produced significant improvements in glycemic
control [57]. Furthermore, successful behavioral stress
management and/or use of anxiolytic medications have
been reported to contribute to long-term glycemic control
in type 2 diabetic patients. Such observations are import-
ant for the clinical practice, since successful behavioral
interventions do not necessarily require staff-intensive
individual training and can be also achieved in routine
clinical settings.
Conclusion
Recent findings advocate the suspected role of chronic
stress in the pathophysiology of metabolic and cardiovas-
cular disease. Chronic activation of the HPA axis and of
sympathoadrenal activity because of modern life stress,
together with changes in eating habits and physical
activity, is suggested to slowly but steadily lead to visceral
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fat accumulation in a large proportion of the population
that is more genetically susceptible, fuelling the growth of
the obesity and diabetes epidemics. Identifying the
pathogenetic mechanisms which facilitate these associ-
ations could lead to novel therapeutic interventions that
may inhibit at an early stage the cascade leading to clinical
manifestations of the metabolic syndrome. At the
moment, effective stress management programs and
treatment of depression may prove to be important tools
in the care of patients at risk or suffering from diabetes
and metabolic syndrome.
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