Perceived Psychological Stress and Serum

Leptin Concentrations in Japanese Men

Rei Otsuka, Hiroshi Yatsuya, Koji Tamakoshi, Kunihiro Matsushita, Keiko Wada, and Hideaki Toyoshima

Abstract
OTSUKA,
REI,
HIROSHI
YATSUYA,
KOJI
TAMAKOSHI, KUNIHIRO MATSUSHITA, KEIKO
WADA, AND HIDEAKI TOYOSHIMA. Perceived
psychological stress and serum leptin concentrations in
Japanese men. Obesity. 2006;14:18321838.
Objective: To examine epidemiologically whether subjects
with higher stress perception levels have higher leptin concentrations.
Research Methods and Procedures: In this cross-sectional
study, the study population comprised 1062 male workers
at local government offices in central Japan. Self-administered questionnaires were distributed in 1997. Awareness of
stress was assessed by the question: Do you have much
stress in your life? and participants were asked to select
from four possible responses: very much, much, ordinary, or little. Blood samples were also collected after
fasting 12 hours overnight to determine serum leptin concentrations.
Results: The mean (standard deviation) age and BMI were
50.2 (6.4) years and 23.3 (2.6) kg/m2, respectively. Crude
leptin concentrations according to stress categories were
2.86, 3.26, 3.32, and 3.54 ng/mL, respectively, and leptin
concentrations adjusted for age, BMI, physical activity,
drinking and smoking habits, overtime work, shift work,
sleep duration, and availability of confidants were 2.96,
3.24, 3.34, and 3.43 ng/mL for little, ordinary, much,
and very much, respectively (p 0.03 by one-way analysis of covariance; p 0.01 by test of linear trend). Significant associations were also observed among the level of

Received for review October 17, 2005.

Accepted in final form July 20, 2006.
The costs of publication of this article were defrayed, in part, by the payment of page
charges. This article must, therefore, be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
Department of Public Health/Health Information Dynamics, Field of Social Life Science,
Program in Health and Community Medicine, Nagoya University Graduate School of
Medicine, Nagoya, Japan.
Address correspondence to Hideaki Toyoshima, 65 Tsurumai-cho, Showa-ku, Nagoya,
Aichi 466-8550, Japan.
E-mail: toyosima@med.nagoya-u.ac.jp
Copyright 2006 NAASO

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OBESITY Vol. 14 No. 10 October 2006

perceived psychological stress and work-related stressors,

variables related to sleep, and other psychological variables.
Discussion: This study showed that subjects who perceived
psychological stress had high leptin levels, which provides
epidemiological evidence that psychological stress may
have the potential effect of increasing blood levels of the
pleiotropic peptide, leptin.
Key words: perceived psychological stress, leptin, crosssectional study, epidemiology, questionnaire

Introduction
Stress, a common phenomenon in modern society, includes a number of reactions that disturb homeostasis, thus
providing a background not only for psychological insufficiency but also somatic diseases (1,2). Stress has been
classically known to activate the sympathoadrenal system
and the hypothalamic-pituitary-adrenocortical (HPA)1 axis
(3,4), which mediates the increase of glucocorticoid level.
Negative feedback control of the HPA axis by increased
glucocorticoid has been documented (4,5).
Recently, continuous infusion of leptin to rhesus monkeys when the HPA axis was activated was reported to
enhance glucocorticoid-negative feedback to this axis, resulting in an attenuation of the neuroendocrine response to
stressors (6). In addition, the ingestion of calorically dense,
highly palatable foods, which is associated with obesity and
increased leptin levels, was also reported to reduce HPA
responsiveness to chronic stress (7). In vitro experiments
have demonstrated leptins inhibition of corticotropin-releasing hormone (CRH) release and have suggested that
circulating leptin limits the activity of the HPA axis, providing another source of negative feedback to that axis (8).
These data, together with observations that the metabolisms
of leptin and glucocorticoid are interconnected, suggest
leptins role in the regulation of stress response (8 12).

1
Nonstandard abbreviations: HPA, hypothalamic-pituitary-adrenocortical; CRH, corticotropin-releasing hormone; ANCOVA, analysis of covariance.

Elevated Leptin Level and Perceived Stress, Otsuka et al.

However, data have been insufficient to posit such an

association in humans. Recently, patients with post-traumatic stress disorder were reported to have higher leptin
concentrations (13). There are no studies, to date, that
examine the association between perceived stress and the
serum leptin concentration in a general population. In a
large sample of middle-aged Japanese men, we examined
whether subjects with higher stress perception levels may
have high serum leptin concentrations.

Research Methods and Procedures

Study Population
The study population was selected from male and female
workers at local government offices in Aichi Prefecture,
central Japan, who participated in a cohort study of cardiovascular diseases (7046 men, 1514 women, 8560 total) (14).
Participants have been followed since 1997, when information about lifestyle-related items was gathered by a selfadministered questionnaire, and blood samples were obtained and stored at the time of their annual health checkups. Of the 6997 male workers 40 to 59 years old at
enrollment, 4831 provided written consent for use of the
information obtained in the questionnaires and the health
check-ups and for the donation of residual serum samples
obtained during the check-ups. We excluded 268 men who
did not return the questionnaire, an additional 15 with
missing data for the stress question, and 10 who did not
undergo weight and height measurements at their checkups. For the present analysis, we retrieved data on 1372
participants from among 4538 men whose blood samples
were taken during fasting to avoid the potential influence of
a meal on their leptin concentrations. Of the remaining
participants, 251 yielded insufficient serum to measure their
leptin concentration. We further excluded 59 men with
missing data for the covariates in the questionnaire, leaving
1062 men eligible for the analysis. The study protocol was
approved by the Ethics Committee of the Nagoya University Graduate School of Medicine (Nagoya, Japan).
Blood Samples
Blood samples were collected after a 12-hour overnight
fast. Serum was isolated immediately, and after some was
used to measure routine health check-up items (serum lipids, glucose, and liver enzymes), the rest was stored at
80C in a deep freezer at the Department of Public Health,
Nagoya University, until determination of serum leptin concentration by radioimmunoassay (Human Leptin Radioimmunoassay Kit; Linco Research, Inc., St. Charles, MO)
at a commercial laboratory in the year 2000.
Perceived Psychological Stress
Awareness of stress was assessed by the question: Do
you have much stress in your life? Participants were asked
to select from among four responses: very much, much,
ordinary, and little.

Other Variables
Smoking status was classified into four levels (never,
past, current smoker of 1 to 24 cigarettes, and 25 or more
per day). Drinking habits were first assessed by the number
of drinking days per week (none, one to three, four to six,
and daily). If other than none, the responses were further
categorized into three levels by weekly consumption (light,
daily alcohol consumption approximately 23 g; moderate,
23 to 46 g; heavy, 46 g or more). Leisure time physical
activity was assessed by two questions about frequency
(seldom, one to three times per month; one to two times per
week; three times or more per week) and intensity (vigorous, moderate, light) of physical activity in their free time.
Three categories were created by combining these two
questions (regularly active, somewhat active, and not very
active) as previously described (15). The number of days
with 2 hours or more overtime work in the previous month
was categorized into two groups (5 days, or 5 days or
more). The presence of shift work was categorized into two
groups (yes, no). The average sleep duration on weekdays
was categorized into two groups (7 hours or 7 hours or
more). Availability of friends one can confide in when
distressed was categorized into two groups (yes, seldom
feeling distressed, or no).
In the questionnaire, the participants were asked whether
they had any of the following complaints regarding sleeping: difficulty initiating sleep, difficulty maintaining sleep,
and poor quality of sleep. We totaled the number of complaints for each individual and grouped them into two
categories (1 or 2). The feeling of subjective well-being
was assessed by the question: Do you have ikigai or hari in
your life? Ikigai is defined as one aspect of psychological
well-being to judge ones life as meaningful and worth
living (16), and hari is something one lives for. The response choices were yes, a lot; yes, so-so; and not
sure. The responses were dichotomized (yes, not yes).
Statistical Analysis
In advance of all statistical analyses, outcome variables
of serum leptin concentrations were logarithmically transformed to approximately achieve normality in the distribution. Crude and adjusted mean concentrations of serum
leptin were then calculated for categories of perceived psychological stress using a general linear model. Adjustments
were made for age and BMI (Model 1). A subsequent
model included variables entered in Model 1 and smoking
status, drinking habit, and physical activity (Model 2). Further adjustment was made for overtime work, shift work,
sleep duration, and availability of confidants (Model 3).
The variables with three or more categories were entered
into the model using dummy variables. Differences among
means were tested by ANOVA or analysis of covariance
(ANCOVA). A test of linear trend was also performed by a
polynomial contrast procedure in a general linear model.
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Elevated Leptin Level and Perceived Stress, Otsuka et al.

Differences in proportions were tested using a 2 test, and

a test of trend in the proportion according to the level of
perceived stress was performed by Mantel-Haenszel 2
(linear-by-linear association). All statistical analyses were
performed with the SPSS/PC statistical program (version
11.5 for Windows; SPSS, Inc., Chicago, IL). All reported
p values were two-sided, and p 0.05 was considered
statistically significant.

Results
The mean (standard deviation) age was 50.2 (6.4) years,
with 58% of subjects 50 to 59 years old. The mean BMI
was 23.3 (2.6) kg/m2; 75% of BMIs were 25 kg/m2. The
mean serum leptin concentration was 3.27 (1.59) ng/mL,
and the Pearsons correlation coefficient with BMI was 0.64
(p 0.01).
Proportions of participants with little, ordinary,
much, and very much perceived mental stress were 7%,
45%, 39%, and 9%, respectively. Mean ages and BMIs of
participants in each stress category were 50.8, 50.6, 49.9,
and 49.5 years and 23.1, 23.3, 23.2, and 23.6 kg/m2 for
little, ordinary, much, and very much, respectively
(Table 1). Differences in age and BMI among stress categories were not statistically significant (age, p 0.25; BMI,
p 0.55 by one-way ANOVA).
Sixty percent of subjects were non-smokers, with 36%
never-smokers, 24% past smokers, and 40% current smokers. The proportion of never-smokers in the very much
stress category was higher than those in other stress categories (42% vs. 35%, 38%, and 31% in much, ordinary,
and little, respectively), but the differences were not statistically significant (p 0.87 by 4 4 2 test). Seventytwo percent of subjects had drinking habits, and proportions
of heavy drinkers in the little stress category were higher
than those in other stress categories (36% vs. 25%, 24%,
and 25% in ordinary, much, and very much, respectively), but those differences, too, were not statistically significant (p 0.31 by 4 4 2 test). Seventy-eight
percent of subjects were classified as having a low level of
physical activity, whereas 14% and 7% of them were somewhat active and regularly active, respectively. Proportions
of subjects who were regularly physically active were
higher in the little stress category than in other stress
categories (14% vs. 7%, 7%, and 6% in ordinary, much,
and very much, respectively; p 0.08 by 3 4 2 test).
The proportion of individuals with 5 days or more overtime work in the previous month was highest in the very
much stress category (42.6%) followed by much stress
category (21.1%) (p 0.01 by 2 4 2 test). The proportion of shift workers in the very much stress category
(22.3%) was higher than other stress categories but that in
the little stress category (16.7%) was also higher than
much or ordinary level of perceived stress categories
(p 0.01 by 2 4 2 test). The proportion of workers with
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the average sleep duration on weekdays of 7 hours was

highest in the very much stress category (53.2%). The
proportion tended to decrease according to the decreasing
level of perceived psychological stress (p 0.01 by test of
linear trend). The proportion of those who had friends in
whom they could confide when distressed was highest in the
little stress category (87.2%) and was linearly associated
with the level of perceived stress (p 0.01 by test of linear
trend). The proportions of those with two or more sleeprelated complaints tended to increase as the level of perceived psychological stress increased from 6.4% in the
little stress category to 23.4% in the very much group
(p 0.01 by 2 4 2 test; p 0.01 by test of linear trend).
The proportion of subjects with ikigai, one aspect of subjective well-being, was highest in the little stress category
(51.3%) and lowest in the ordinary stress category
(34.2%) (p 0.03 by 2 4 2 test).
Crude leptin concentrations according to stress categories
were 2.85, 3.26, 3.32, and 3.54 ng/mL for little, ordinary, much, and very much, respectively (Table 2).
The adjustment with covariates other than BMI slightly
attenuated the association (Model 1), but the differences
among means were highly statistically significant (p
0.01). Multivariable-adjusted leptin concentrations with
age, BMI, physical activity, and drinking and smoking
habits (Model 2) were 2.95, 3.23, 3.35, and 3.42 ng/mL for
little, ordinary, much, and very much, respectively
(p 0.02 by one-way ANCOVA; p 0.01 by test of linear
trend). Further adjustment for overtime work, shift work,
sleep duration, and availability of confidants attenuated the
association, but the differences in the leptin level remained
statistically significant (p 0.03 by one-way ANCOVA;
p 0.01 by test of linear trend). The estimated leptin
concentrations in Model 3 were 2.96, 3.24, 3.34, and 3.43
ng/mL for little, ordinary, much, and very much,
respectively.

Discussion
The present study revealed that subjects who reported an
awareness of higher stress in their daily lives had significantly higher serum leptin levels than those in other stress
categories. The association was independent of the degree
of obesity as measured by BMI, age, and lifestyle variables.
Such a finding is consistent with the results of a previous
study with post-traumatic stress disorder patients who were
found to be hyperleptinemic (13), suggesting that the leptin
concentration may be used as a marker for perceived daily
stress. There are, however, other experimental studies reporting that chronic stress did not increase leptin levels
(17,18). Evidence regarding humans is sparse, and further
studies are needed to examine the association between
chronic stress and leptin levels.
Stress has been classically known to activate the sympathoadrenal system and the HPA axis, which mediates the

Elevated Leptin Level and Perceived Stress, Otsuka et al.

Table 1. Characteristics of study subjects according to stress categories (n 1062)

Age (mean, years)

BMI (mean, kg/m2)
Smoking status (n, %)
Never
Past
Current (1 to 24 cigarettes/d)
Current (25 cigarettes/d)
Drinking habit (n, %)
None
Light
Moderate
Heavy
Physical activity (n, %)
Not very active
Somewhat active
Regularly active
Number of days with 2 hours of
overtime work in previous
month (n, %)
Less than 5 days
5 days or more
Shift work (n, %)
No
Yes
Average sleep on weekdays (n, %)
Less than 7 hours
7 hours or more
Availability of friends one can
confide in when distressed
(n, %)
Yes
Seldom distressed or no
Number of sleep-related complaints
(n, %)
1 or less
2 or more
Feel subjective well-being (n, %)
Yes
Not yes

Little
(n 78)

Ordinary
(n 477)

Much
(n 413)

Very much
(n 94)

50.8
23.1

50.6
23.3

49.9
23.2

49.5
23.6

0.25
0.55

0.14
0.26

24 (30.8)
20 (25.6)
18 (23.1)
16 (20.5)

179 (37.5)
107 (22.4)
102 (21.4)
89 (18.7)

144 (34.9)
104 (25.2)
93 (22.5)
72 (17.4)

39 (41.5)
20 (21.3)
16 (17.0)
19 (20.2)

0.87

0.50

18 (23.1)
19 (24.4)
13 (16.7)
28 (35.9)

137 (28.7)
105 (22.0)
102 (21.4)
119 (24.9)

120 (29.1)
112 (27.1)
82 (19.9)
99 (24.0)

25 (26.6)
26 (27.7)
20 (21.3)
23 (24.5)

0.31

0.16

51 (65.4)
16 (20.5)
11 (14.1)

383 (80.3)
61 (12.8)
33 (6.9)

327 (79.2)
59 (14.3)
27 (6.5)

71 (75.5)
17 (18.1)
6 (6.4)

0.08

0.21

70 (89.7)
8 (10.3)

433 (90.8)
44 (9.2)

326 (78.9)
87 (21.1)

54 (57.4)
40 (42.6)

0.01

0.01

65 (83.3)
13 (16.7)

436 (91.4)
41 (8.6)

353 (85.5)
60 (14.5)

73 (77.7)
21 (22.3)

0.01

0.01

21 (26.9)
57 (73.1)

143 (30.0)
334 (70.0)

151 (36.6)
262 (63.4)

50 (53.2)
44 (46.8)

0.01

0.01

68 (87.2)
10 (12.8)

314 (65.8)
163 (34.2)

226 (54.7)
187 (45.3)

45 (47.9)
49 (52.1)

0.01

0.01

73 (93.6)
5 (6.4)

443 (92.9)
34 (7.1)

362 (87.7)
51 (12.3)

72 (76.6)
22 (23.4)

0.01

0.01

40 (51.3)
38 (48.7)

163 (34.2)
314 (65.8)

158 (38.3)
255 (61.7)

39 (41.5)
55 (58.5)

0.03

0.93

p*

Trend p

* p Value by one-way ANOVA for continuous variables and by 2 test for categorical ones.
Trend test was performed by a polynomial contrast procedure in general linear model or by Mantel-Haenszel 2 (linear-by-linear
association).

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Table 2. Leptin concentrations according to stress categories

Little
(n 78)

Ordinary
(n 477)

Much
(n 413)

Very much
(n 94)

p*

Trend p

2.85
2.91
2.95
2.96

3.26
3.24
3.23
3.24

3.32
3.35
3.35
3.34

3.54
3.42
3.42
3.43

0.02
0.01
0.02
0.03

0.01
0.01
0.01
0.01

Crude mean
BMI- and age-adjusted mean (Model 1)
Multivariate-adjusted mean (Model 2)
Multivariate-adjusted mean (Model 3)

* p Value by ANOVA for crude mean differences and by ANOVA for adjusted means.
Trend test was performed by polynomial procedure.
BMI, age, smoking status, drinking habit, and physical activity were adjusted (Model 2). Categorical variables were entered into the
models using dummy variables.
The variables included in Model 2 and overtime work, shift work, sleep duration, and availability of confidants (Model 3).

increase in glucocorticoid levels. Increased levels of glucocorticoids are reportedly capable of stimulating the synthesis and secretion of leptin (19 21). Once the stressor is
gone, the neuroendocrine responses are normally terminated
(22). Negative feedback control of the HPA axis by increased glucocorticoids has been documented (4,5). Circulating leptin is also speculated to limit the activity of the
HPA axis based on the observation that leptin inhibits CRH
release, providing another source of negative feedback to
this axis (8). Then, a question arises why the increased
levels of leptin do not inactivate the HPA axis in a state of
chronic stress, given our findings that individuals who perceived higher stress had increased leptin levels. Leptin
resistance of the hypothalamus may be involved in the
pathogenesis of this inability of leptin to affect HPA axis
activity (23). At the same time, failure to terminate this
response is observed in various conditions of an overactivated HPA axis (37,22,24,25) with a subsequent attenuation of the pituitary neuroendocrine response. Disruption of
the glucocorticoid-negative feedback system is observed in
approximately one-half of human depressives (26), and a
similar condition is induced in animals by chronic stress (7).
This disruption is thought to involve a down-regulation of
glucocorticoid receptors in the feedback sites of the brain
(26). Decreases in the activity of 11-hydroxysteroid dehydrogenase are also suggested to exist in individuals with
chronic stress and might be associated with an attenuation
of HPA axis response to glucocorticoid-negative feedback
(27). Our finding of increased leptin levels in individuals
who perceived more psychological stress implies that leptin
might have been increased to attenuate the stress response
resulting from persistent HPA axis activation by chronic
stressors, a phenomenon that may be considered as a purported biological reaction to the harmful effect of stress
response to the host. It is possible to speculate that the
association of stress with obesity or eating disorders may be
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mediated by an elevated glucocorticoid level owing to persistent HPA activation and/or an alteration in the serum
leptin level (28,29).
In the absence of any stressor when the HPA axis is not
activated, leptin administration was reported to increase the
CRH mRNA expression and subsequent circulating levels
of corticosterone and adrenocorticotropic hormone dosedependently (30). This may well be an effect linked to
leptins anorexic action. Also, leptin reportedly increased
sympathetic outflow through activation of CRH-containing
central nervous system pathways (31,32).
Experimental studies of psychological stress have reported increased sympathetic activity, which could lead to
increased ambulatory blood pressure levels (33), pulse rates
(34), and platelet aggregation (35); reduced insulin sensitivity (36); and endothelial dysfunction (37). Hyperleptinemia has also been associated with high blood pressure,
increased pulse rate, metabolic syndrome, and increased
risk of cardiovascular diseases (38 40). It is reasonable to
speculate that the adverse health consequences of psychological stress may partly be mediated by the high leptin
levels observed in subjects with chronic stress perception. In
addition, individuals with higher levels of psychological
stress should be regarded as having allostatic load reflected
by their high leptin levels (22).
Some limitations of the present study warrant discussion.
First, we used a single simple question about self-perceived
psychological stress rather than compiling scores of psychological stress. We did not provide a specific definition or
criteria regarding the meaning of these categories or examples of the stressors in the questionnaire. A negative emotion such as depression, which has been associated with
leptin concentrations, was not an item in the questionnaire
either. Thus, in future studies, the evaluation of individual
stress needs to be more precisely determined, and a negative
emotion like depression must also be considered. Because

Elevated Leptin Level and Perceived Stress, Otsuka et al.

there are no studies yet that have examined leptin levels in

relation to perceived psychological stress levels in human
general populations, and disagreement exists whether stress
is associated with an increased leptin level, further investigation with a more detailed assessment of perceived stress is
essential to confirm the present findings.
We considered that people who feel stressed in their daily
lives are probably exposed to some chronic stressor. Indeed,
the subjects with high perceived stress were more likely to
have overtime work. The sleep duration on weekdays
tended to decrease, and the proportion of subjects with two
or more sleep-related complaints tended to increase according to the increase in the level of perceived stress. The
proportion of subjects who lacked confidants was linearly
associated with the increased level of perceived stress.
Furthermore, we observed positive associations between
the level of perceived stress and the level of job-related
stressors measured using a simplified questionnaire based
on Karaseks job demand control model in this population in a different year (41). We also observed a reasonable
degree of reliability of the questionnaire item about daily
stress perception in a 5-year interval (Spearman correlation
coefficient r, 0.49; and consistency, 56%).
Other investigators also used the same question item to
assess the level of perceived psychological stress and revealed the association with cardiovascular diseases or colorectal cancer (1,42). However, in general, the level of perceived stress does not always accord with the strength or
quantity of the stressor because of the difference in the way
individuals perceive the same situation and their general
state of physical health (22). It may also be possible that a
level of leptin is determined by how an individual perceives
the stressor, not by the level of stressor itself. Further study
is needed in living humans to clarify the associations among
the level or the quantity of stressor, the individuals perception, and the leptin level.
A second limitation is related to the use of BMI to control
for a possible confounding of the total fat mass. Although
BMI is reported to represent a reliable and valid measure of
fat mass, it does not perfectly reflect the degree of adiposity,
nor does it provide information regarding adipose tissue
distribution. Although we found and adjusted for the statistically insignificant difference in BMI among subjects in a
range of stress categories, there may be a residual confounding of fat mass not explained by BMI. However, BMI was
more strongly associated with diabetes incidence than was
waist circumference among young Japanese Americans
(43), suggesting that it may be used as a more reliable
measure of adiposity in that ethnic group than in others. The
cross-sectional nature of the present study implies a possibility that a high leptin level may lead an individual to
perceive greater stress than someone with a lower leptin
concentration would.

In conclusion, the present study showed that subjects who

perceived psychological stress had high leptin levels, thus
providing epidemiological evidence that psychological
stress has the potential effect of increasing the blood level of
the pleiotropic peptide, leptin. If this finding is confirmed
by future investigations, it is even possible that the leptin
concentration could be used as a marker for perceived daily
stress.

Acknowledgment
This work was supported, in part, by Grants 17390185 (to
H.T.), 18590594 (to K.T.), and 17790384 (to H.Y.) from the
Ministry of Education, Culture, Sports, Science and Technology and the Japan Atherosclerosis Prevention Fund.
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