Clinical Science (2001) 100, 145–150 (Printed in Great Britain)
Relationships between baseline serum leptin
levels and 2-year changes in body mass index,
blood pressure and metabolic parameters in
Japanese male adolescents and middle-aged men
Hiroshi HIROSE*†, Ikuo SAITO*†, Toshihide KAWAI*, Minako TSUJIOKA*†
Hiroshi KAWABE*† and Takao SARUTA*
*Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan,
and †Health Centre, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
A
B
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We and others have reported that serum leptin levels are positively correlated with body mass
index (BMI), blood pressure and heart rate (HR) in cross-sectional clinical studies. However, only
a few longitudinal studies have focused on the relationships between leptin, BMI and blood
pressure. The present study was performed to elucidate the relationships between baseline
serum leptin levels and 2-year changes in BMI, blood pressure, HR and metabolic parameters in
314 Japanese male adolescents aged 16–17 years and in 225 Japanese men aged 30–63 years.
Height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, fasting plasma
glucose (FPG), serum lipids [total cholesterol (TC), triacylglycerols (TG), high-densitylipoprotein cholesterol (HDL-C) and low-density-lipoprotein cholesterol (LDL-C)], uric acid
(UA), insulin and leptin levels were measured in the morning after an overnight fast. In the male
adolescents, serum leptin levels in 1996 (log [leptin’96]) were significantly correlated with BMI,
SBP, mean blood pressure and HR in 1998 (r l 0n40, 0n13, 0n11 and 0n14, respectively). The
percentage change in BMI per year (∆BMI) was negatively correlated with log [leptin’96], even
after adjustment for baseline BMI (r lk0n12, P l 0n030). In men aged 30–63 years, log [leptin’96]
was also positively correlated with BMI’98, SBP’98, DBP’98, FPG’98, TC’98, log [TG’98], LDLC’98 and UA’98 (all P 0n05), and negatively correlated with HDL-C’98, ∆BMI, ∆FPG, ∆TC and
∆LDL-C. The relationship between log [leptin’96] and ∆TC was significant, even after adjustment
for initial BMI (r lk0n15, P l 0n023). These findings therefore suggest that serum leptin levels
are correlated with subsequent decreases in BMI and TC in Japanese men.
INTRODUCTION
Obesity is characterized by excessive accumulation of
body fat and has become an important health problem in
industrialized societies, as it is a risk factor for diabetes
mellitus, hypertension, hyperlipidaemia and atherosclerotic diseases, due to insulin resistance and\or the
resultant hyperinsulinaemia [1–4]. Obesity is known to
be related to hypertension [5], although the mechanism(s)
are not completely understood [6]. Animal studies have
Key words : blood pressure, fasting plasma glucose, leptin, lipid profile, weight change.
Abbreviations : BMI, body mass index ; ∆BMI (etc.), percentage change in BMI per year (etc.) ; DBP, diastolic blood pressure ; FPG,
fasting plasma glucose ; HDL-C, high-density-lipoprotein cholesterol ; HR, heart rate ; LDL-C, low-density-lipoprotein cholesterol ;
MBP, mean blood pressure ; SBP, systolic blood pressure ; TC, total cholesterol ; TG, triacylglycerol ; UA, uric acid ; the suffixes ’96
and ’98 refer to data obtained in 1996 and 1998 respectively.
Correspondence : Dr Hiroshi Hirose (e-mail hhirose!hc.cc.keio.ac.jp).
# 2001 The Biochemical Society and the Medical Research Society
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H. Hirose and others
suggested that activation of the sympathetic nervous
system is associated with obesity-related hypertension
[7].
The mouse obese (ob) gene was identified using the
positional cloning technique [8], and subsequent studies
have revealed that the ob gene product, leptin [9], is
expressed mainly in adipocytes and acts as a satiety factor
that reduces food intake and increases energy expenditure
via binding to its receptors [9–13]. Serum leptin levels
have been reported to increase with degree of obesity
[14–16], suggesting the occurrence of increased leptin
resistance in obese subjects. Recent studies have indicated
that human obesity is associated with marked sympathetic activation [17], and several animal studies have
shown that leptin increases sympathetic nervous system
activity [18,19] and arterial blood pressure [20,21]
We and others have reported that serum leptin levels
are positively correlated with body mass index (BMI)
[14–16,22], blood pressure [23,24] and heart rate (HR)
[23,25] in cross-sectional clinical studies. To our knowledge, however, only a few longitudinal studies have
focused on the relationships between leptin, BMI and
blood pressure (e.g. leptin’s effects on weight change in
Pima Indians [26]). The present study was therefore
performed in order to elucidate the relationship between
baseline serum leptin levels and changes in BMI, blood
pressure, HR, plasma glucose, lipid profile, etc., in a 2year follow-up study of Japanese male adolescents and
middle-aged men.
Part of this work was presented at the 22nd Annual
Meeting of the Japanese Society of Hypertension in
Takamatsu on October 22, 1999, and at the 43rd Annual
Meeting of the Japan Diabetes Society in Nagoya, on
May 26, 2000.
total cholesterol (TC), triacylglycerol (TG ; triglyceride),
high-density-lipoprotein cholesterol (HDL-C), lowdensity-lipoprotein cholesterol (LDL-C), uric acid (UA),
insulin and leptin concentrations were measured in the
morning after an overnight fast.
Measurements
Systolic blood pressure (SBP), diastolic blood pressure
(DBP) and HR in subjects of both age groups were
measured with an automatic electronic sphygmomanometer (BP-103i II ; Nippon Colin, Komaki, Japan),
twice in the sitting position after resting for at least 3 min,
as described previously [22,23]. Plasma glucose and lipids
were assayed by routine automated laboratory methods.
Serum insulin concentrations were measured with a
commercially available RIA kit from Eiken Chemical
Co. (Tokyo, Japan), and leptin concentrations with an
RIA kit from Linco Research Inc. (St. Charles, MO,
U.S.A.), as described previously [22,23].
Statistical analyses
All statistical analyses were performed using the
StatView2 program for Macintosh (version 4.5-J ; Abacus
Concepts Inc., Berkeley, CA, U.S.A.). Because the serum
leptin, insulin and TG levels were normally distributed
after log transformation, the logarithms of these parameters were used for regression analyses. Data analysis
included the calculation of Pearson’s correlation
coefficients and partial correlation analyses. All data are
expressed as meanspS.D., and P 0n05 was considered
statistically significant.
RESULTS
METHODS
Subjects
The subjects of this study consisted of 314 Japanese male
adolescents aged 16–17 years and 225 Japanese men aged
30–63 years in 1996, who came for annual medical checkups in both 1996 and 1998. Subjects with diabetes
mellitus, endocrine diseases, or significant renal or
hepatic disease, and those taking antihypertensive drugs,
systemic corticosteroids or lipid-lowering drugs, were
excluded. This study was carried out in accordance with
the Declaration of Helsinki (1989) of the World Medical
Association, and the study protocol was approved by the
Ethics Committees of Health Center and the Department
of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. Informed consent was obtained from
each subject after full explanation of the purpose, nature
and risk of all procedures used. Height, weight, blood
pressure, HR, fasting plasma glucose (FPG), and serum
# 2001 The Biochemical Society and the Medical Research Society
Relationships between baseline serum leptin
and insulin levels, blood pressure, HR and
metabolic parameters in a 2-year follow-up
study of Japanese male adolescents
As shown in Table 1, the serum leptin levels in 1996
(log [leptin’96]) were significantly correlated with 1998
values for body weight, BMI, SBP, mean blood pressure
(MBP) and HR. Moreover, log [leptin’96] was negatively
correlated with the percentage change in BMI per year
(∆BMI) (Table 1 and Figure 1A ; P 0n001), but not with
∆SBP, ∆DBP or ∆HR. This negative correlation between
log [leptin’96] and ∆BMI was significant, even after
adjustment for baseline BMI (r lk0n12, P l 0n030).
As shown in Table 2, log [insulin’96] was also positively
correlated with SBP’98, DBP’98, MBP’98 and HR’98 (all
P 0n05), and negatively correlated with ∆BMI and
∆HR (r lk0n11 and k0n15 respectively). However, the
correlation of ∆BMI with log [insulin’96] was weaker
than with log [leptin’96].
Leptin, body weight and metabolic parameters
Table 1 Pearson’s correlations (upper) and partial correlation coefficients (lower) between baseline leptin levels and
clinical parameters in 314 Japanese male adolescents aged
16–17 years
Table 2 Pearson’s correlations (upper) and partial correlation coefficients (lower) between baseline insulin levels and
clinical parameters in 314 Japanese male adolescents aged
16–17 years
Regression coefficients are given for the correlation of each parameter with
log [leptin’96]. Significance : * P 0n05, ** P 0n01, *** P 0n001.
Regression coefficients are given for the correlation of each parameter with
log [insulin’96]. Significance : * P 0n05, ** P 0n01, *** P 0n001.
r
Parameter
1996 data
Unadjusted
Body weight
BMI
SBP
DBP
MBP
HR
0n49***
0n55***
0n21***
0n14*
0n18**
0n18**
After adjustment for baseline BMI
Body weight
0n04
BMI
–
SBP
0n07
DBP
0n08
MBP
0n08
HR
0n20***
r
1998 data
0n35***
0n40***
0n13*
0n09
0n11*
0n14*
k0n05
k0n15**
k0n01
0n01
k0n01
0n14*
Percentage change
per year
Parameter
k0n27***
k0n27***
k0n07
k0n05
k0n06
k0n05
Unadjusted
Body weight
BMI
SBP
DBP
MBP
HR
0n14*
0n17**
0n17**
0n14*
0n16**
0n28***
0n09
0n11
0n14*
0n12*
0n14*
0n14*
k0n09
k0n11*
k0n01
k0n02
k0n01
k0n15**
k0n08
k0n12*
k0n07
k0n06
k0n07
k0n07
After adjustment for baseline BMI
Body weight
k0n02
BMI
–
SBP
0n12*
DBP
0n12*
MBP
0n13*
HR
0n28***
k0n04
k0n08
0n10
0n09
0n10
0n14*
k0n03
k0n06
k0n01
k0n02
k0n01
k0n16**
Relationships between baseline serum leptin
and insulin levels, blood pressure, HR and
metabolic parameters in a 2-year follow-up
study of adult and middle-aged Japanese
men
As shown in Tables 3 and 4, log [leptin’96] in men aged
30–63 years was positively correlated with BMI’98,
1996 data
1998 data
Percentage change
per year
SBP’98, MBP’98, DBP’98, FPG’98, TC’98, log [TG’98],
LDL-C’98 and UA’98 (all P 0n05), and negatively
correlated with HDL-C’98. Log [leptin’96] was also
negatively correlated with ∆BMI (Figure 1B), ∆FPG
(Figure 2A), ∆TC (Figure 2B) and ∆LDL-C, but not with
∆SBP, ∆DBP or ∆HR. The correlations of log [leptin’96]
with SBP’98, MBP’98 and HDL-C’98 were stronger than
with the 1996 values (SBP’96, MBP’96 and HDL-C’96).
Figure 1 Negative correlations between baseline leptin levels and ∆BMI in 314 Japanese male adolescents (A) and in 225
Japanese men aged 30–63 years (B)
# 2001 The Biochemical Society and the Medical Research Society
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H. Hirose and others
Table 3 Pearson’s correlations (upper) and partial correlation coefficients (lower) between baseline leptin levels and
clinical parameters in 225 Japanese men aged 30–63 years
Regression coefficients are given for the correlation of each parameter with
log [leptin’96]. Significance : * P 0n05, ** P 0n01, *** P 0n001.
r
Parameter
1996 data
1998 data
Percentage change
per year
Unadjusted
Age
BMI
SBP
DBP
MBP
HR
k0n01
0n62***
0n16*
0n22***
0n20**
0n04
k0n01
0n59***
0n18**
0n22**
0n21**
0n03
–
k0n16*
0n08
0n06
0n08
k0n05
0n06
k0n06
0n02
0n07
0n05
0n07
–
k0n07
k0n03
0n01
k0n01
k0n09
After adjustment for baseline BMI
Age
0n06
BMI
–
SBP
0n03
DBP
0n07
MBP
0n06
HR
0n13
Table 4 Pearson’s correlations (upper) and partial correlation coefficients (lower) between baseline leptin levels and
serum metabolites in 225 Japanese men aged 30–63 years
Regression coefficients are given for the correlation of each parameter with
log [leptin’96]. Significance : * P 0n05, ** P 0n01, *** P 0n001.
r
Parameter
1996 data
1998 data
Percentage change
per year
Unadjusted
FPG
TC
log TG
HDL-C
LDL-C
UA
0n31***
0n22***
0n32***
k0n26***
0n31***
0n24***
0n22**
0n15*
0n30***
k0n29***
0n17*
0n20**
k0n14*
k0n16*
0n02
k0n01
k0n15*
k0n09
0n09
0n15*
0n16*
k0n05
0n14*
0n07
k0n09
k0n15*
0n01
k0n04
k0n08
k0n07
After adjustment for baseline BMI
FPG
0n16*
TC
0n23***
log TG
0n16*
HDL-C
k0n03
LDL-C
0n24***
UA
0n11
The negative correlation between log [leptin’96] and ∆TC
was significant, even after adjustment for baseline BMI
(Table 4 ; r lk0n15, P l 0n023).
# 2001 The Biochemical Society and the Medical Research Society
Log [insulin’96] was also positively correlated with
SBP’98, DBP’98, MBP’98 and HR’98 (all P 0n05),
but the correlations were weaker than those with
log [leptin’96]. Log [insulin’96] was not correlated with
the percentage change per year in any of the parameters
measured (results not shown).
DISCUSSION
The baseline serum leptin levels of both the male
adolescent group and the adult and middle-aged men
group in the present study were positively correlated with
their BMI and blood pressure values 2 years later. In the
adult and middle-aged men, log [leptin’96] was also
positively correlated with FPG’98, TC’98, log [TG’98],
LDL-C’98 and UA’98. Animal studies on the effects of
leptin on the cardiovascular system have suggested that
leptin activates the sympathetic nervous system [18,19],
increases arterial pressure [20,21] and increases insulin
sensitivity [27,28]. Serum leptin levels in our previous
cross-sectional study [23] were also positively correlated
with blood pressure. In that study, HR was correlated with leptin only in the adolescents, suggesting that
leptin-induced activation of the sympathetic nervous
system may contribute to obesity-related hypertension,
especially in adolescents. We speculate that the aetiology
in adult and middle-aged men may be more complicated
because of confounding factors, including sodium retention, insulin resistance itself and\or atherosclerosis.
In the present study, baseline serum leptin levels in
both the male adolescent group and the adult and middleaged men group were negatively correlated with ∆BMI.
These findings are partly compatible with the results of
the 3-year follow-up study on Pima Indians [26], showing
that the mean plasma leptin concentration was significantly lower in 19 weight gainers ( 3 kg\year) than in
17 weight-stable subjects (p0n4 kg) after adjustment for
initial percentage body fat. Although it is unfortunate
that we were unable to measure serum or urine catecholamines or basal metabolic rate in the present study, we
hypothesize that high serum leptin levels increase basal
metabolic rate and fat oxidation via increased sympathetic
tone, especially in adolescents. In the adult and middleaged men, however, a decrease in appetite caused by
leptin, or merely a weight oscillation, may have been the
main factor in the decline in BMI.
In the present study, serum leptin levels were negatively correlated with ∆TC, independent of baseline
BMI, in men aged 30–63 years. Silver et al. [29] have
suggested that defective HDL particle uptake and
recycling in ob\ob hepatocytes (from leptin-deficient
mice) play a role in the deterioration of plasma HDL
protein and cholesterol levels. In the present study,
log [leptin’96] was negatively correlated with both HDLC’96 and HDL-C’98, but not with ∆HDL-C. Instead,
Leptin, body weight and metabolic parameters
Figure 2
Negative correlations betweenbaselineleptin levels and ∆FPG (A) and ∆TC (B) in 225 Japanese men aged 30–63 years
∆LDL-C and ∆TC were negatively correlated with
baseline leptin levels. We speculate that the effects of
leptin on appetite and body weight may have been
associated with later amelioration of glucose and lipid
metabolism in the present study.
It is unclear if the results obtained here were related to
alterations in the production or the clearance of leptin.
High serum leptin levels in obese subjects suggest that
they are attributable to increased secretion from an excess
amount of fatty tissue. However, these obese subjects are
supposed to show leptin resistance to some extent.
Although the mechanism(s) of leptin resistance is not
clear, recent studies in vitro have shown that leptin
receptor (Ob-Rb) expression in neuroblastoma cells
decreased too 18 % of control levels following a 24 h
incubation with 50 ng\ml leptin [30]. Other possible sites
of leptin resistance are the blood–brain barrier [31] and
post-receptor pathways, including STAT3 (signal transducer and activator of transcription 3) proteins [32].
To summarize, baseline serum leptin levels of male
adolescents were negatively correlated with ∆BMI, even
after adjustment for initial BMI. Also, the baseline serum
leptin levels of adult and middle-aged men were negatively correlated with ∆BMI, ∆FPG, ∆TC and ∆LDL-C,
and the correlation with ∆TC was significant even after
adjustment for initial BMI. These findings suggest that
serum leptin levels are correlated with subsequent
decreases in BMI and TC in Japanese men.
ACKNOWLEDGMENTS
We thank Shuji Oguchi, Shinobu Noji, Masami
Masumoto and Eiko Takeshita (Department of Laboratory Medicine, Keio University Hospital) for their
technical assistance with RIAs. This study was supported
in part by research grants (to H. H.) from Keio University.
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Received 21 February 2000/22 June 2000; accepted 12 October 2000
# 2001 The Biochemical Society and the Medical Research Society