stress and abdominal obesity

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2001 The International Association for the Study of Obesity. obesity reviews 2, 7386 73

Do stress reactions cause abdominal obesity

and comorbidities?

expression denotes a psychological situation of having used

up all endogenous energy, ending up in a psychological

insufficiency that makes further efforts at work as well as

a normal psychosocial life severely disturbed, and requires

a long period of recovery. This condition is apparently

becoming increasingly prevalent, and is supposed to be due

to the complex, competitive environment of current society.

obesity reviews

Department of Heart and Lung Diseases,

Sahlgrens Hospital, University of Gteborg,

Sweden

Received 31 August 2000; revised 30

October 2000; accepted 6 November 2000

Address reprint requests to: Department of

Heart and Lung Diseases, Sahlgrens

Hospital, University of Gteborg, Sweden

E-mail: [email protected]

P. Bjrntorp

SummaryStress embraces the reaction to a multitude of poorly defined factors that

disturb homeostasis or allostasis. In this overview, the activation of the

hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system

have been utilized as objective measurements of stress reactions. Although long-

term activation of the sympathetic nervous system is followed by primary hyper-

tension, consequences of similar activation of the HPA axis have not been clearly

defined. The focus of this overview is to examine whether or not repeated acti-

vation of these two stress centres may be involved in the pathogenesis of abdom-inal obesity and its comorbidities. In population studies adrenal hormones show

strong statistical associations to centralization of body fat as well as to obesity.

There is considerable evidence from clinical to cellular and molecular studies that

elevated cortisol, particularly when combined with secondary inhibition of sex

steroids and growth hormone secretions, is causing accumulation of fat in vis-

ceral adipose tissues as well as metabolic abnormalities (The Metabolic Syn-

drome). Hypertension is probably due to a parallel activation of the central

sympathetic nervous system. Depression and the small baby syndrome as well

as stress exposure in men and non-human primates are followed with time by

similar central and peripheral abnormalities. Glucocorticoid exposure is also fol-

lowed by increased food intake and leptin resistant obesity, perhaps disrupting

the balance between leptin and neuropeptide Y to the advantage of the latter. Theconsequence might be stress-eating, which, however, is a poorly defined entity.

Factors activating the stress centres in humans include psychosocial and socio-

economic handicaps, depressive and anxiety traits, alcohol and smoking, with

some differences in profile between personalities and genders. Polymorphisms

have been defined in several genes associated with the cascade of events along the

stress axes. Based on this evidence it is suggested that environmental, perinatal

and genetic factors induce neuroendocrine perturbations followed by abdominal

obesity with its associated comorbidities.

Keywords: adrenals, central, cortisol, leptin, neuropeptide Y, Obesity, stress.

obesity reviews (2001) 2, 7386

Introduction

Stress is a common phenomenon in the industrialized

world, and provides a background not only to psychologi-

cal reactions and insufficiency but also, when protracted,

probably somatic disease. The condition burned out now

often occurs in the current discussion of diseases. This


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roendocrina consequences of potential stressors as well

as associated endocrine, anthropometric, metabolic and

haemodynamic factors.

Measurements of saliva cortisol were used as indicators

of HPA axis activity in these studies, and the blood pres-

sure and heart rate values as indicators of the activity of

the sympathetic nervous system. In women it became

evident that free testosterone was most likely an index of

central regulation of adrenal activity because it correlated

strongly with dihydroepiandrosterone sulphate (DHEAS),

a steroid excreted almost exclusively by the adrenals, as

well as with various cortisol measurements. Free testo-

sterone and DHEAS were, therefore, also used as a mea-

surement of adrenal activity because of the advantage in

comparison with cortisol of showing less variation over the

day (14,unpublished).

HPA axis perturbations and centralizationof body fat

The waist/hip circumference ratio (WHR) and abdominal

sagittal diameter are estimations of centralization of body

fat, where the sagittal diameter shows the strongest corre-

lations with the mass of intra-abdominal, visceral depot fat

(15). These masses are highly dependent on the endocrine

status. This field has been reviewed in detail, where refer-

ences to original publications are found (16). In brief, cor-

tisol as well as sex steroid and growth hormones are

involved. Cortisol activates lipoprotein lipase, the gate-

keeper of lipid accumulation in adipocytes. Furthermore,

cortisol in the presence of insulin inhibits the lipid mobi-lizing system. Since these events are mediated by the GR,

and the density of these receptors is higher in intra-

abdominal, visceral than other fat depots, the activity of

cortisol leading to accumulation of fat will be accentuated

in this adipose tissue. This is seen dramatically in Cushings

syndrome, and disappears with successful therapy. This is

summarized in (Fig. 2).

Growth hormone exerts powerful inhibition of the

lipoprotein lipase activity and activates the lipid mobiliz-

ing system. The sex steroid hormones exert permissive

effects on growth hormone action. The density of the

androgen receptor is particularly high in visceral adipose

tissue, and is upregulated by testosterone. Consequently, a

combination of these hormones has, in principle, actions

counteracting those of cortisol (Fig. 3).

In summary, this means that elevation of cortisol is fol-

lowed by visceral fat accumulation. Furthermore, low sex

steroid and growth hormone secretions will have the same

consequence, because of the insufficient counteraction

against cortisol effects, and a combination of these abnor-

malities will have powerful consequences to direct a larger

than normal fraction of total body fat to visceral depots

(Fig. 4).

76 Do stress reactions cause abdominal obesity and comorbidities P. Bjrntorp obesity reviews

2001 The International Association for the Study of Obesity. obesity reviews 2, 7386

This interpretation of data from cellular and molecular

studies is in agreement with observations in the integrated

system in vivo. Increased cortisol secretion in Cushings

syndrome as well as after corticosteroid treatment of

disease is typically followed by an increase of central, vis-

ceral adipose tissue volume. Such conditions are also

usually associated with low levels of growth and sex steroid

hormone concentrations, because it is well established that

activation of the HPA axis is followed by inhibition of the

central gonadal and growth hormone axes at several levels

(17) (Fig. 4). Hormonal, as well as visceral fat mass, abnor-

Figure 2 Cortisol binds to glucocorticoid receptors, which have a

particularly high density in visceral fat depots. Lipoprotein lipase is

activated via gene transcription and enzyme stabilization. Cortisol also

inhibits lipid mobilization in the presence of insulin. Both these activities

lead to triglyceride accumulation and retention in visceral adipose

tissue (16).

High density of androgen receptors

Testostero increases androgen

receptor density

Lipoprotein lipase inhibited

Lipid mobilisation stimulated

Triglyceride accumulation and

retention diminished

Figure 3 Testosterone is acting via the androgen receptor, the density

of which is increased by autoregulation. The receptor has a higher

density in visceral than other fat depots. By inhibition of lipid

accumulation and stimulation of lipid mobilizing mechanisms, visceral

depots are diminishing. These actions provide a permissive

amplification of growth hormone effects (16).


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malities are disappearing with removal of cortisol excess.

In conditions with primary deficiency of growth hormone,

such as in hypophysectomy with substitution of all other

hormones than growth hormone, there is clearly an

increase of visceral fat mass, disappearing with growth

hormone substitution. In analogy, excess growth hormonesecretion, such as in acromegaly, is associated with small

intra-abdominal fat depots. Similar examples are found for

the sex steroid hormones. With menopause and decreased

concentrations of 17b estradiol, visceral fat masses are ele-

vated, and diminish with hormone replacement therapy.

With testosterone deficiency in men, occurring in some

men with ageing, visceral fat masses increase, and are

diminished with adequate testosterone replacement

therapy. The tendency for elevation of visceral fat masses

with age in both genders may, thus, be due primarily to the

relatively low secretion of growth and sex steroid hor-

mones, which are following ageing (16).

In summary, there is an excellent agreement between in

vivo observations and cellular, molecular data indicating

that excess cortisol, as well as low growth and sex steroid

hormones are followed by elevated visceral fat mass. The

evidence indicates that these associations are causally

mediated.

As mentioned above, it is important to realize that an

increased activity of the HPA axis is followed by inhibition

of both the pituitary gonadal as well as the growth hormone

axes (17). From this it follows that a decrease of sex steroid

and growth hormones may in fact be a consequence of stress

factors acting over the HPA axis. Stress may, therefore, be

active on the factors accumulating visceral depot of fat bothvia both elevated cortisol secretion as well as the secondary

decrease of sex steroid and growth hormones (Fig. 4).

The next question then is whether or not these associa-

tions in examples of clinical, endocrine entities are valid in

the general population. In the populations mentioned

above this has been examined in both men and women. In

the men there are strong relationships between the body

mass index (BMI), the WHR, the waist circumference and

the sagittal diameter on the one hand, and various cortisol

measurements on the other as seen in Table 1. It should be

noted that these correlations are most tight with cortisol

secretion regulated by an abnormally functioning HPAaxis, particularly after challenges, such as after lunch, and

reported peceived stress (14). Furthermore, low testos-

terone and/or growth hormone concentrations alone show

such associations, growth hormone secretion estimated as

the concentration of insulin-like growth factor I (18). In

addition statistical path analyses indicate that both mea-

surements of cortisol and, negatively, of testosterone and/or

growth hormone are directly followed by the WHR or the

sagittal abdominal diameter (18) (Fig. 5). These observa-

tions indicate that the WHR and sagittal abdominal diam-

eter are dependent on elevated cortisol and/or low sex

steroid and growth hormones, and that these anthropo-

metric measurements of centralization of body fat might

serve as reasonable approximations of the long-term

endocrine abnormalities associated with stress.

It should be observed that the BMI shows equally strong

associations as the measurements of centralization of body

fat to the cortisol measurements (see Table 1 and Fig. 5).

This will be discussed separately in the next section.

In women the situation is partly different. As briefly men-

tioned above free testosterone is probably a measurement

of adrenal activity in women because of its close associa-

tion with DHEAS and cortisol measurements. As seen in

obesity reviews Do stress reactions cause abdominal obesity and comorbidities P. Bjrntorp 77


Figure 4 The chronically activated hypothalamic-pituitary-adrenal axis

inhibits the secretion of growth hormone (GH), testosterone (T) and 17b

estradiol (E2), which counteract cortisol effects. The net result will be

accumulation of visceral fat (16,17). CRH: Corticotropin releasing

hormone. GnRH: Gonadotropin releasing hormone. GHRH: Growth

hormone releasing hormone.

Table 1 Correlations between hormones and anthropometric variablesin men (14,18)

p-values

BMI WHR W D

Normal HPA axisTotal cortisol 0.035 ns ns ns

Lunch cortisol 0.005 ns


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ference or sagittal abdominal diameter. Taken together,

these observations open up the possibility that both obesity

and centralization of body fat may have the same origin,

namely often repeated or chronic activation of the HPA

axis.

There is interesting experimental evidence to suggest that

glucocorticoids might be involved in the pathogenesis of

obesity, also elucidating the mechanisms involved. Recent

experiments using the rat show that adrenalectomy is fol-

lowed by marked sensitivity to leptin. With graded replace-

ment of glucocorticoids leptin sensitivity is diminished in

parallel, and with administration of larger doses of gluco-

corticoids overeating is induced, resulting in obesity in spite

of elevated leptin levels (22). These experiments demon-

strate that corticosteroids induce leptin secretion and a

condition of leptin resistant obesity, induced by gluco-

corticoid excess. Human obesity is also characterized by

elevated leptin levels (23), a leptin resistant type of

obesity. The localization of this resistance is apparently notat the level of the leptin receptor to a significant degree

(24), and its origin is currently not known.

There is further evidence from experimental studies in

humans. Elevated levels of leptin follow administration of

glucocorticoids with variations in duration and apparently

different effects in obesity and between the genders

(2527). In one study food intake was measured by a tech-

nique where food was available freely in liquid form from

a dispenser. This method allows full control of energy

intake, but may not be considered to mirror natural con-

ditions. It is also known that this method is followed by

overconsumption of energy. Nevertheless, the group takingglucocorticoids was, in spite of elevated leptin levels, con-

suming more energy than the control group (27).

We have recently repeated this study in 15 moderately

overweight women who received 25 mg prednisolone

during 7 days. Leptin levels rose in all women, who also

showed increased food intake measured with an eating

monitor. The effect was apparently not diminished over the

time of measurements. Effects on total energy intake, mea-

sured by the less precise technique of diet history, could not

be discovered, although there was a tendency to increased

carbohydrate intake (unpublished).

Taken together this evidence suggests that glucocorti-

coids are able to increase food intake in spite of elevated

leptin levels. This opens up the interesting possibility that

cortisol may be involved, not only in the centralization

mechanisms of body fat, but also in the accumulation of

total body fat, that is obesity, provided that these effects

are remaining with a sufficiently long duration. If this turns

out to be the case cortisol may induce leptin resistant

obesity, the common form of obesity in humans. This

problem is of particular interest against the background

that obesity, in general, is associated with overproduction

of cortisol, although this is apparently more pronounced in

central obesity (28). This is an area of considerable inter-

est for further research.

Recent experiments suggest the possibility that the other

regulatory axis of food intake regulation, the neuropeptide

Y (NPY) system, might also be involved in the effects of

glucocorticoids. Stress-induced cortisol-secretion seems to

be followed by elevated NPY secretion (29). Increased cir-

culating levels have been reported after strenuous physical

stress (30) as well as after mental stress (31). However, in

the rat restraint stress diminishes NPY in the arcuate

nucleus (32) and NPY mRNA in the amygdala (33), but

after repeated stress and high salt intake plasma levels of

NPY rise (34). Although these results indicate relationships

between stress-related cortisol and peripheral NPY levels

in humans, the problem needs further evaluation.

In summary, the evidence available suggests that gluco-

corticoids blunt the efficiency of the inhibiting branch of

food intake control, the leptin system. There is also a pos-

sibility that glucocorticoids can stimulate the food intakebranch, the NPY system, and therefore disrupt the balance

of food intake regulation to the advantage of NPY effects.

If confirmed, this could, in the long-run, be expected to be

followed by overeating and obesity. This hypothesis is sum-

marized schematically in Fig. 6.

With this background one may wonder if cortisol

elevation with stress might induce the phenomenon of

stress-eating, and thereby contribute to the generation of

obesity. The basic concept for stress-eating to occur is that

increased food intake would be a response to emotional



Figure 6 Neuroendocrine background to abdominal obesity, a

hypothesis. With cortisol excess (right panel) the balanced system (left

panel) the secretion of neuropeptide Y (NPY) is stimulated and leptin

effects blunted (leptin resistance). This is followed by increased food

intake and elevated total body fat mass (outer circle) with too large a

fraction in visceral depots (inner circle), directed there by excess

cortisol and low gonadal and growth hormones. The result will be

abdominal obesity, as a consequence of stress-eating.


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stress, and that eating would subsequently diminish the dis-

tress, presumably via central opioids.

Animal data with acute physical stressors have shown

varying results (35), while stressful housing conditions

have been shown to be followed by increased food intake

(36). Also in human studies conflicting results have been

reported. Preoperative stress showed no effect (37), while

results of another study suggest overeating before the stress

of school examinations. This seemed to be more pro-

nounced for fat intake and in girls (38). There are con-

siderable individual variations. A reasonably stable

predictor of stress-induced eating seems to be a restrained

attitude towards eating. This area has recently been sub-

jected to a comprehensive review (35). Another critical

recent review concludes that the evidence now available is

flawed by various errors, making conclusions difficult (39).

Stress-eating is complex to study for several reasons.

First, the definition of stress is highly variable and indi-

vidually different as described in a section above. Second,the presumed end result, increased food intake in relation

to stress, is not easy to measure accurately, and studies

have often been relying on self-reports. In this review

stress has been defined as a measurable neuroendocrine-

autonomic response. Studies of stress-eating utilizing such

measurements might be clarifying.

This area is of particular interest when considering the

background of the current obesity epidemic in industrial-

ized parts of the world. This has started in parallel with a

presumed decrease of physical activity, but also in parallel

with the development of a very competitive society, where

overeating due to stress might be involved.

Are neuroendocrine-endocrine perturbationssecondary to abdominal obesity?

The considerations above, both as far as fat distribution

and obesity, suggest that the associated neuroendocrine-

endocrine abnormalities in, particularly, central obesity is

the primary factor followed by abdominal obesity and its

complications. The increased cortisol secretion in central

obesity is now well established (28). There is also the pos-

sibility that this is secondary to the obese state.

Cortisol turn over has been reported to be elevated, due

to a peripheral metabolism to less active metabolites. This

would, in turn, increase cortisol secretion secondarily due

to a less efficient feedback inhibition of the HPA axis. If

this is the correct interpretation then it is difficult to under-

stand why only central obesity would have elevated corti-

sol and peripheral symptoms of a relative hypercortisolism,

and not peripheral obesity at the same BMI. An apparent

solution to this problem would be to examine what is left

of the central regulatory abnormalities after treatment

to normal body weight. Unfortunately the results of

such interventions become inconclusive, because weight



decrease below a certain steady state, obese or lean, results

in secondary neuroendocrine and autonomic adaptations

which confound interpretations. Another way to interven-

tion is to attempt to normalize the neuroendocrine and

endocrine abnormalities by, for example, substitution with

sex steroids or growth hormone to levels normal for age.

Such studies have shown clear global improvements or

even normalization of abnormalities in abdominal obesity

(40).

The crucial intervention is, of course, that on cortisol

secretion. This is difficult to perform because there are,

unfortunately, currently no safe means for this purpose.

Cushings syndrome may, however, be taken as a model.

When the hypercortisolaemia is removed, the condition

is cured. Furthermore, and the other way around, when

other primates than humans are exposed to standardized

submissive stress, an identical picture as that seen in

abdominally obese humans is develops (3). The consistent

statistical association between abdominal obesity andstress-inducing environments in humans (see next section)

is another argument in the same direction, because it

seems unlikely that such environments would follow

moderate abdominal obesity. Further arguments will be

discussed below in relation to depression and the small

baby syndrome.

Associations between environmentalfactors and neuroendocrine and autonomicstress reactions

In population studies of men and women several associa-tions have been found between stress reactions measured

as neuroendocrine and autonomic consequences, as

described above, and a number of environmental factors.

In our earlier reports, where information was obtained

from the study of men born in 1913 and from the study of

women in Gothenburg, associations were sought mainly

between measurements of the WHR and environmental

factors. The rational for using the WHR as a surrogate

measurement of long-term stress was reviewed in a pre-

ceding section. The study of men comprised approximately

1000 subjects, and the study of women about 1400 sub-

jects, probands in cohorts of about 200 in different age

strata from both before and after menopause. In men, asso-

ciations were found between the WHR and poor educa-

tion, low social class, and physical types of poorly paid

work. In addition divorce and living alone showed positive

correlations. This was also found for alcohol consumption

and smoking (41).

Similar findings were made in women with some inter-

esting differences. Women are apparently less sensitive to

having experienced divorce, and to live alone. Furthermore,

particularly consumption of strong liquor showed correla-

tions to the WHR. In women there was also information


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on psychiatric symptoms or equivalents, including depres-

sive moods, consumption of antidepressant drugs and

anxiolytics. In addition, sleeping difficulties were frequent

(42). Similar findings have subsequently also been reported

in studies from other laboratories (43).

These previous population studies were not primarily

designed for analyses of the relationships between stress

and somatic abnormalities, making the possibilities for

detailed analyses fairly limited. The information obtained

was, however, of sufficient interest to encourage further

studies directly focused on this problem. Therefore, new

populations were selected, where data were assembled to

allow more detailed examinations of the relationships

between environment, stress-reactions, and somatic abnor-

malities. In these recent studies the previous observations

have been replicated with some additions. The psychiatric

relationships to the WHR were also found in men (44). In

addition, certain personality types were more prone to

show such associations, particularly men with dependent,anxiety prone personalities (45).

In early studies the association to the WHR was clearly

stronger than those to the BMI, in fact the latter associa-

tions were in certain instances negative (41,42). In the new

studies strong associations are found not only to the WHR,

but also to the BMI. An apparent explanation for this dif-

ference might be that there is a 30-year difference between

the birth year of the men, and between 25 and 40 years in

the women. During this period of time there has been

a considerable increase in the prevalence of obesity in

Sweden. This might have caused a greater impact of obesity

in the newly performed studies.In the new studies measurements of the activity of the

HPA axis were included, allowing studies of the direct asso-

ciations between environmental and genetic (see below)

factors and the regulation of neuroendocrine and auto-

nomic centres, as well as the consequences for somatic vari-

ables. In essence, similar results were obtained with the

measurements of HPA-axis activity as with the anthropo-

metric measurements, reemphasizing that measurements of

centralization of body fat masses might be considered as

useful indicators of long-term activation of neuroendocrine

abnormalities (46,47). The direct measurements of detailed

HPA-axis activity give, however, more detailed information

on the current status of the kinetics of neuroendocrine reg-

ulations, and better possibilities to trace the origin of the

abnormalities.

Physical inactivity may be involved in the pathogenesis

of abdominal obesity. This is indicated by answers to ques-

tionnaires by both men and women (50,unpublished).

Men with socioeconomic handicaps often have physical

types of works (41). Physical training is followed by adap-

tations towards a lower activity of the central sympathetic

nervous system with low pulse rate and blood pressure

(49). This would presumably be the reverse with physical

inactivity. Intervention studies separating physical inac-

tivity and moderate daily activity with information on

neuroendocrine and autonomic adaptations do not seem

to have been performed. There is no doubt that physical

activity even at moderate levels would decrease the pre-

ponderance to develop obesity. Whether physical inactivity

would have an additional, specific effect on abdominal

obesity is, however, not clarified.

Metabolic and haemodynamic consequencesof stress reactions

The focus of this review has been the association between

stress and obesity, particularly central, abdominal, visceral

obesity. There are, however, other statistical companions to

stress with abdominal obesity. These are metabolic pertur-

bations, with insulin resistance in a central position, which

are characteristic of the Metabolic Syndrome. These pertur-

bations are also likely to be consequences of the endocrineabnormalities following stress reactions, with elevated corti-

sol secretion as well as associated decreases in growth and

sex steroid hormones. These mechanisms are largely known,

and this field has recently been reviewed (50).

Frequently associated hypertension has been con-

sidered to be a consequence of hyperinsulinaemia, follow-

ing insulin resistance (51). It is, however, equally likely that

the hypertension associated with the Metabolic Syndrome

is caused by parallel activation of the both stress centres,

the HPA axis and the central sympathetic nervous system.

These centres are closely functionally coupled (17), and it

is difficult to activate one centre without activating theother (Fig. 1). This problem has also been reviewed in detail

recently (50).

Depression

Depression is a classical condition with an activated HPA

axis and central sympathetic nervous system. Depression is

known to be followed by a substantially increased risk to

develop cardiovascular disease and type 2 diabetes melli-

tus in prospective population studies. Recent data show

that depression or depressive symptoms are associated with

somatic symptoms characterizing the Metabolic Syndrome,

including visceral accumulation of body fat. Treatment

with a serotonin reuptake inhibitor seems to be followed

by improvement not only of the neuroendocrine but also

the metabolic abnormalities in men with depressive symp-

toms (52).

This information suggests the possibility that the risk

factor pattern in depression follows the neuroendocrine

perturbations of that condition, and therefore the risk of

somatic disease is increased. This then supports the sug-

gested pathway for development of the Metabolic Syn-

drome and central obesity, described above.




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The small baby syndrome

The small baby syndrome is a condition where subjects,

born small for gestational age, develop central obesity

and the Metabolic Syndrome at adult age. Recently it has

been shown that such individuals display perturbations

of the regulation of the HPA axis, much of the same char-

acter as described above for subjects in the population

studies. The background seems to be preprogramming of

the regulation of central neuroendocrine axes, which is

possible to induce in experimental studies in rats by agents

such as glucocorticoids, lipopolysaccharides, cytokines

and immune or stress challenges to the pregnant mother.

It, therefore, seems possible that similar neuroendocrine-

autonomic, anthropometric, metabolic and haemodynamic

abnormalities found in the population may in fact be due

to perinatal conditions. The quantitative importance of

this pathway in relation to environmaental pressures in

adult life and genetic abnormalities is not yet known(53).

Prospective studies of stress exposure

The best evidence for the correctness of the interpretations

presented above of the pathogenesis of the Metabolic Syn-

drome and central accumulation of visceral fat comes,

however, from controlled experiments in a non-human

primate. When Cynomolgus monkeys are subjected to psy-

chosocial stress, some individuals respond with a depres-

sive, defeated reaction. These monkeys show enlarged

adrenals, a diminished suppression of cortisol secretionby a low dose dexamethasone, decreased sex steroids,

elevated androgens in females, visceral fat accumulation,

the Metabolic Syndrome and early signs of coronary

atherosclerosis and glucose intolerance (54). This is an

end result of controlled, long-term stress exposure and is

identical to the results we have reported in humans

with psychosocial stress as summarized above, and, thus,

offers strong support to the contention that stress may be

the first part of the chain of events leading to somatic

disease.

Similar observations may in fact be made in men. Men

exposed to poor working conditions develop with time a

gradually increasing visceral fat mass and the Metabolic

Syndrome (13,46). Stress-induced cortisol secretion is

increasing and the dexamethasone suppression is becoming

blunted (46). These observations are also supportive of the

interpretations provided for the connection between envi-

ronmental stress and somatic risk factors.

Genetic factors

An update of the genetics of human obesity has recently

appeared (55). There are, clearly, genetic factors involved



in the neuroendocrine and autonomic aberrations

described above. For example, homozygotic twins show

closely similar diurnal secretion of cortisol (56). Associa-

tion studies suggest several possibilities for polymorphisms

of candidate genes involved in the syndrome described in

this study. The control of the activity of the HPA axis pro-

vided by central glucocorticoid receptors shows abnormal-

ities in the men examined with abnormal HPA-axis

regulation (14,46) (women, to be examined). This is asso-

ciated with a polymorphism of the glucocorticoid receptor

gene. A longer allele (4.5kb) than that considered normal

(2.3kb), obtained after digestion with the restriction

enzyme Bcl I, is associated with a poor control of stimu-

lated cortisol secretion (57) as well as with abdominal

obesity, insulin resistance and hypertension (5760).

Homozygotes (4.5/4.5kb) are found in about 14% of the

men. Heterozygotes (4.5/2.3kb) also show associations,

although less pronounced. The localization of this poly-

morphism is in the first introne, and it may, therefore, notbe excluded that it has a functional significance for initia-

tion of transcription.

Another polymorphism is found in the 5-flanking (pro-

moter) domain of the glucocorticoid receptor gene locus

and is associated with total cortisol secretion (61). Both

these polymorphisms suggest that there might be variants

of functional importance in the 5end or promoter region

of the glucocorticoid receptor gene. We are, therefore, cur-

rently attempting to sequence these domains. A microsatel-

lite in the first coding exon of the gene is apparently normal

(unpublished). We could not confirm in our material of

men that a polymorphism in this exon is associated withobesity (62), which was recently reported (63).

In the women studied potential genes associated with

hyperandrogenicity have been examined. Focus has been

set on microsatellite length, which apparently shows large

variations in genes regulating steroid hormone metabolism

and signals to target cells. This is a novel aspect of genetic

associations to malfunction and disease. Short stretches of

microsatellites in, for example, the transactivating domain

of the androgen receptor gene result in a receptor with

strong signalling power and vice versa. These quantitative

relationships seem particularly interesting in the pathogen-

esis of certain human diseases, such as diabetes type 2 or

hypertension, where a gradual, quantitative deterioration

of regulatory mechanisms occurs. The microsatellite

stretches are apparently instabile between generations,

making these types of polymorphisms interesting also for

evolutionary changes (64).

Testosterone is transformed into 17b estradiol by the

enzyme aromatase. The aromatase gene has a microsattelite

in the 5th intron where short length variants have previ-

ously been shown to be associated with disease in women

(65). A short microsatellite with tetranucleotide (TTTA)

repeats was found to be associated with elevated free


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testosterone and low 17b estradiol levels (unpublished),

which is the expected result of a poorly functional enzyme.

The activity of the enzyme has, however, not yet been deter-

mined. Furthermore, a short microsatellite with


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The neuroendocrine-autonomic stress reaction is proba-

bly followed by metabolic abnormalities, the Metabolic

Syndrome, via the endocrine perturbations following long-

term, repeated activation of the HPA axis, as well as ele-

vation of blood pressure via a parallel activation of the

central sympathetic nervous system.

Depression may serve as a model for the condition

described, because here the neuroendocrine-autonomic

abnormalities are similar as well as apparently the somatic

risk factor pattern and increased risk to develop somatic

disease. Furthermore, the small baby syndrome, character-

ized by central obesity and the Metabolic Syndrome, has

recently been found to be associated with similar central

abnormalities, which in experimental studies are possible

to induce by manipulations during pregnancy. The strong-

est support for the correctness of the interpretations offered

for a chain of submissive stress-neuroendocrine-autonomic

perturbations-anthropometric, metabolic and haemody-

namic abnormalities comes, however, from controlledexperiments in non-human primates, where this has been

directly shown. A similar situation can be identified in men

subjected to stressful working conditions.

The evidence summarized in this study, thus, suggests

that abdominal obesity is a condition with a neuroen-

docrine background affecting the HPA axis as well as the

central sympathetic nervous system with subsequent inhi-

bition of the gonadal and growth hormone axes. These

might be primary events where subsequently the leptin

and NPY systems become unbalanced, favouring the latter.

The background to such a development is likely of central

origin via factors that are commonly defined as stress. Inorder for abdominal obesity to develop a positive energy

balance must be established. The neuroendocrine cascade

described may facilitate an increased energy intake in

susceptible subjects. A decreased physical activity will also

be followed by a positive energy balance and might be

another consequence of current environments. It has been

suggested that there is a closer control of energy balance

at higher levels of energy output, and less tight regulation

at lower levels of physical activity. One might speculate

that the lack of stress releaving function of physical activ-

ity might add to the impact of the syndrome described

above.

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