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The Journal of Clinical Endocrinology & Metabolism 87(6):2764 –2769
Copyright © 2002 by The Endocrine Society
Decreased Plasma Adiponectin Concentrations in
Women with Dyslipidemia
MIYAO MATSUBARA, SHOJI MARUOKA,
AND
SHINJI KATAYOSE
Division of Endocrinology and Metabolism, Otaru City General Hospital (M.M.), Otaru 047-8550; and Otsuka Assay
Institute (S.M., S.K.), Sapporo 060-0061, Japan
Adiponectin, the gene product of the adipose most abundant
gene transcript 1, is a novel adipocyte-derived peptide that
has been considered to have antiinflammatory and antiatherogenic effects. To characterize the relationship between
adiponectin and lipids metabolism, we measured fasting
plasma adiponectin concentration by ELISA, serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and apolipoprotein (apo) levels in 352 nondiabetic women, 16 – 86 yr old, with a wide range of body weight
[body mass index (BMI), 14.8ⴚ36.3 kg/m2].
Plasma adiponectin concentrations in women with the
highest tertile of TG (1.69 mM < ⬃) were decreased, compared
with the middle (1.13 < ⬃ <1.69) or lowest tertile of TG (⬃
<1.13) (5.9 ⴞ 0.5 vs. 7.5 ⴞ 0.3, 9.2 ⴞ 0.2 ␮g/ml; P < 0.005, 0.001).
Plasma adiponectin with the lowest tertile of HDL-C (⬃ <1.16
mM) was decreased, compared with the middle (1.16 < ⬃ <
1.81) or highest tertile of HDL-C (1.81 < ⬃) (5.7 ⴞ 0.5 vs. 7.8 ⴞ
0.2, 10.1 ⴞ 0.4 ␮g/ml; both P < 0.001). These relationships had
A
DIPOSE TISSUE IS now known to express and secrete
a variety of hormones and cytokines, including leptin,
TNF␣, and plasminogen activator inhibitor type 1, which
may contribute to the development of cardiovascular diseases (1– 4), and these are collectively known as adipocytokines (5). Adiponectin, the gene product of the adipose most
abundant gene transcript 1 (apM1) gene, which is exclusively
and abundantly expressed in white adipose tissue, is a 244amino-acid protein with high structural homology to collagen VIII, X, and complement C1q (6). Because adiponectin
accumulates in injured vessel walls and dose-dependently
inhibits TNF␣-induced cell adhesion in human aortic endothelial cells, which is an early step of atherosclerosis, it has
been considered that adiponectin may have antiatherogenic
properties (7–10). This protein was also identified independently by the other three groups, using different approaches,
and has been reported as Acrp30 (11), AdipoQ (12), or
gelatin-binding protein 28 (13). Adiponectin is reported to be
abundant in human circulation, with plasma levels in the
microgram-per-milliliter range, thus accounting for approximately 0.01% of total plasma protein (14). Plasma adiponectin concentrations were found to be decreased in patients
with obesity (14), type 2 diabetes (15), and cardiovascular
disease (7).
Dyslipidemia is a highly prevalent disorder that is assoAbbreviations: apo, Apolipoprotein; BFM, body fat mass; BMI, body
mass index; BP, blood pressure; BUN, blood urea nitrogen; HDL-C,
high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol; TC, total cholesterol; TG, triglyceride.
similar tendencies after adjustment for BMI, body fat mass,
age, or diastolic blood pressure. Adiponectin was negatively
correlated with serum TG (r ⴝ ⴚ0.33, P < 0.0001), atherogenic
index [(total cholesterol ⴚ HDL-C)/HDL-C] (r ⴝ ⴚ0.34, P <
0.0001), apo B (r ⴝ ⴚ0.45, P < 0.0001), or apo E (r ⴝ ⴚ0.29, P <
0.05), and positively correlated with serum HDL-C (r ⴝ 0.39,
P < 0.0001) or apo A-I levels (r ⴝ 0.42, P < 0.002). Those negative
relationships became stronger after adjusting for BMI or body
fat mass. The slightly positive correlation between adiponectin and age, blood urea nitrogen, or creatinine levels was also
observed (all P < 0.001).
These results indicate that high-TGnemia and low-HDLCnemia are associated with low plasma adiponectin concentrations in nondiabetic women. Further efforts must now be
targeted to determine whether adiponectin causes these lipid
abnormalities and thus whether it is partly responsible for the
atherogenic risk seen in the metabolic syndrome. (J Clin Endocrinol Metab 87: 2764 –2769, 2002)
ciated with decreased longevity and increased morbidity
from a variety of diseases, including insulin resistance, obesity, hypertension, and cardiovascular disease. These coexistences have been variously called metabolic syndrome X,
the deadly quartet, or multiple risk factor clustering syndrome (16 –19). In the present cross-sectional study, we examined the relationship between plasma adiponectin and
lipid metabolism in a large group of Japanese nondiabetic
subjects. Because sex difference had been reported in plasma
adiponectin (14), serum triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), uric acid, and body fat mass
(BFM) percent (20, 21), we chose women only.
Subjects and Methods
Subjects
Three hundred fifty-two Japanese women residing in Hokkaido, Japan, 16 – 86 yr old (mean ⫾ se, 54.0 ⫾ 0.8 yr), excluding those with birth
control pill use, diabetes mellitus (fasting blood glucose ⱖ7.0 mm or
blood glucose ⱖ11.1 mm at 2-h value after 75 g glucose loading), renal
failure [serum creatinine ⱖ159 ␮mol/liter or blood urea nitrogen (BUN)
ⱖ10.7 mmol/liter], or untreated endocrine diseases, were included in
this crosssectional study. Participants were recruited and examined
between October 1999 and October 2000 and were in follicular phase
among menstruating women. Systolic and diastolic blood pressure (BP)
were measured in the right arm of seated participants by using a mercury-column sphygmomanometer positioned near eye level. Approximately 30, 21% of females had systolic (ⱖ160 mm Hg) and/or diastolic
hypertension (ⱖ90 mm Hg); 48 were receiving calcium antagonists
and/or angiotensin converting enzyme inhibitors. All anthropometric
measures were made with the participant wearing light clothes and no
shoes. Body mass index (BMI) was calculated as weight in kilograms
divided by the square of the height in meters. BFM was determined by
2764
Matsubara et al. • Decreased Adiponectin in Dyslipidemia
J Clin Endocrinol Metab, June 2002, 87(6):2764 –2769 2765
TABLE 1. The clinical characteristics in studied female subjects
Mean ⫾
No.
Age (yr)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
BMI (kg/m2)
BFM (%)
Serum uric acid (␮M)
Creatinine (␮M)
BUN (mM)
Fasting blood glucose (mM)
Serum TC (mM)
TG (mM)
HDL-C (mM)
LDL-C (mM)
Atherogenic index
apo A-I (mg/dl)
B (mg/dl)
E (mg/dl)
(Range)
SE
352
54.0 ⫾ 0.8
144.1 ⫾ 1.0
80.9 ⫾ 0.5
22.9 ⫾ 0.2
30.2 ⫾ 0.3
273.6 ⫾ 4.2
53.0 ⫾ 1.8
5.1 ⫾ 0.1
5.27 ⫾ 0.04
5.28 ⫾ 0.05
1.07 ⫾ 0.03
1.65 ⫾ 0.02
3.11 ⫾ 0.03
2.4 ⫾ 0.05
159.9 ⫾ 4.6
111.8 ⫾ 3.7
4.6 ⫾ 0.2
Prevalence (%)
(16– 86)
(94–200)
(60–114)
(14.8–36.3)
(12.1– 47.9)
(23.8– 624.5)
(26.5–150.3)
(1.6–10.4)
(3.61– 6.94)
(2.87– 8.74)
(0.20–3.66)
(0.57–3.21)
(0.62–5.95)
(0.5–11.2)
(56–288)
(48–199)
(2.2–7.9)
30.2 (⭌160)
21.2 (⭌90)
26.4 (⭌25.0)
20.6 (⭌327)
34.4 (⭌5.69)
12.2 (⭌1.69)
7.4 (⬍1.16)
12.2 (⭌4.14)
16.8 (⭌3.0)
Atherogenic index, (TC-HDL-C)/HDL-C; Prevalence, abnormal percentage among participants.
TABLE 2. The correlations between several parameters and plasma adiponectin before and after adjusting for body composition
Factor
Age
Systolic BP
Diastolic BP
Serum uric acid
Creatinine
BUN
Serum TC
TGa
HDL-C
LDL-C
Atherogenic indexa
apo A-I
B
E
a
Plasma adiponectina
Adiponectin/BMIa
Adiponectin/BFM (%)a
r
P
r
P
r
P
0.215
0.053
⫺0.061
⫺0.090
0.212
0.218
0.031
⫺0.333
0.387
⫺0.029
⫺0.336
0.415
⫺0.448
⫺0.285
⬍0.0001
0.3235
0.2534
0.0908
0.0004
0.0003
0.5645
⬍0.0001
⬍0.0001
0.5832
⬍0.0001
0.001
⬍0.0001
0.041
0.134
⫺0.002
⫺0.147
⫺0.117
0.176
0.180
⫺0.066
⫺0.383
0.408
⫺0.141
⫺0.428
0.404
⫺0.495
⫺0.318
0.0116
0.9748
0.0056
0.0286
0.0035
0.0028
0.2150
⬍0.0001
⬍0.0001
0.0082
⬍0.0001
0.003
⬍0.0001
0.022
0.089
⫺0.022
⫺0.154
⫺0.122
0.168
0.159
⫺0.111
⫺0.411
0.404
⫺0.183
⫺0.455
0.387
⫺0.495
⫺0.300
0.0981
0.6846
0.0040
0.0229
0.0055
0.0087
0.0384
⬍0.0001
⬍0.0001
0.0006
⬍0.0001
0.005
⬍0.0001
0.031
Log-transformed statistics.
bioelectrical impedance analysis: this was the mean value determined
using both a TBF-541 body fat analyzer (Tanita/Stellar Innovations, Inc.,
Tokyo, Japan) and an HBF-301 body fat analyzer (Omron, Tokyo, Japan)
(20, 21). All females provided informed consent. The clinical characteristics of the studied subjects are shown in Table 1.
Biochemical analyses
Blood glucose was measured by the glucose oxidase method, and
serum lipids [total cholesterol (TC), TG, HDL-C], apolipoprotein (apo)
A-I, apo B, apo E, creatinine, BUN, and uric acid were measured using
commercially available kits. Low-density lipoprotein cholesterol
(LDL-C) was estimated using the Friedewald’s formula, and the atherogenic index was calculated by the formula: (TC ⫺ HDL-C)/HDL-C.
Blood samples for measurement of fasting plasma adiponectin concentrations were drawn with EDTA-aprotinin tubes and immediately
placed on ice. All tubes were centrifuged at 4 C for collection of plasma
and stored at ⫺80 C until analyses at Otsuka Assay Institute, Tokushima,
Japan. Adiponectin was determined using a validated sandwich ELISA
employing an adiponectin-specific antibody, which has been demonstrated by Arita et al. (14). Five plasma samples were used to evaluate
intra- and interassay coefficients of variation, which, for adiponectin,
ranged from 2.1– 4.2% (mean, 3.3) and 5.9 –9.2% (mean, 7.4), respectively.
Statistical analyses
Subjects were stratified into tertiles of serum TG levels (⬃ ⬍1.13 mm,
1.13 ⱕ ⬃ ⬍ 1.69, 1.69 ⱕ ⬃), HDL-C levels (⬃ ⬍1.16 mm, 1.16 ⱕ ⬃ ⬍ 1.81,
1.81 ⱕ ⬃), TC levels (⬃ ⬍4.65 mm, 4.65 ⱕ ⬃ ⬍ 5.69, 5.69 ⱕ ⬃), LDL-C
levels (⬃ ⬍3.10 mm, 3.10 ⱕ ⬃ ⬍ 4.14, 4.14 ⱕ ⬃), or atherogenic index
(⬃ ⬍1.5, 1.5 ⱕ ⬃ ⬍ 3.0, 3.0 ⱕ ⬃), because serum TG ⱖ1.69 mm, TC ⱖ5.69
mm, and LDL-C ⱖ4.14 mm were considered to be elevated, and HDL-C
⬍1.16 mm to be decreased in Japanese women, by Japan Atherosclerosis
Society criteria (21). The differences across tertiles of plasma adiponectin, before and after adjustment for BMI or BFM, were tested with
ANOVA. Two-way ANOVA tests were done to determine possible
relations for plasma adiponectin concentration between tertiles of TG or
HDL-C and the stratified parameters, such as BMI (⬃ ⬍22.0 kg/m2,
22.0 ⱕ ⬃ ⬍ 25.0, 25.0 ⱕ ⬃), age (⬃ ⬍40 yr, 40 ⱕ ⬃ ⬍ 55, 55 ⱕ ⬃), or
diastolic BP (⬃ ⬍80 mm Hg, 80 ⱕ ⬃ ⬍ 90, 90 ⱕ ⬃). Because preliminary
analyses indicated that the distributions of plasma adiponectin, TG, and
atherogenic index were skewed, log transformation was used, which
yielded more normally distributed data. Linear regression was performed to determine which factor (among age, systolic and diastolic BP,
BMI, BFM, TC, TG, HDL-C, LDL-C, atherogenic index, fasting blood
glucose, creatinine, BUN, and uric acid) correlated with log-transformed
adiponectin before and after adjusting for BMI or BFM. Results are
expressed as mean ⫾ sem. A P value less than 0.05 was considered to
be statistically significant.
Results
As shown in Table 1, subjects covered a wide range of age,
BP, and body composition. Table 2 shows the simple relationship between adiponectin and selected variables for all
2766
J Clin Endocrinol Metab, June 2002, 87(6):2764 –2769
Matsubara et al. • Decreased Adiponectin in Dyslipidemia
TABLE 3. Plasma adiponectin concentrations in each tertiles of lipid parameters (serum TG, HDL-C, TC, LDL-C and atherogenic index)
before and after adjusting for body composition
(n)
Serum TG (mM)
1.69 ⬉ TG
1.13 ⬉ TG ⬍ 1.69
TG ⬍ 1.13
Serum HDL-C (mM)
1.81 ⬉ HDL
1.16 ⬉ HDL ⬍ 1.81
HDL ⬍ 1.16
Serum TC (mM)
5.69 ⬉ TC
4.65 ⬉ TC ⬍ 5.69
TC ⬍ 4.65
Serum LDL䡠C (mM)
4.14 ⬉ LDL
3.10 ⬉ LDL ⬍ 4.14
LDL ⬍ 3.10
Atherogenic index (AI)
3.0 ⬉ AI
1.5 ⬉ AI ⬍ 3.0
AI ⬍ 1.5
Adiponectin (␮g/ml)
Adiponectin/BMI
Adiponectin/BFM (%)
(43)
(78)
(231)
5.9 ⫾ 0.5ab
7.5 ⫾ 0.3
9.2 ⫾ 0.2b
0.26 ⫾ 0.02cb
0.32 ⫾ 0.02
0.43 ⫾ 0.01b
0.19 ⫾ 0.02db
0.24 ⫾ 0.01
0.34 ⫾ 0.01b
(121)
(205)
(26)
10.1 ⫾ 0.4bb
7.8 ⫾ 0.2
5.7 ⫾ 0.5b
0.48 ⫾ 0.02bb
0.35 ⫾ 0.01
0.25 ⫾ 0.02e
0.37 ⫾ 0.02bb
0.27 ⫾ 0.01
0.18 ⫾ 0.02e
(121)
(140)
(91)
8.7 ⫾ 0.3
8.3 ⫾ 0.3
8.3 ⫾ 0.4
0.38 ⫾ 0.02
0.38 ⫾ 0.02
0.41 ⫾ 0.02
0.28 ⫾ 0.01
0.29 ⫾ 0.01
0.33 ⫾ 0.02
(43)
(138)
(171)
7.9 ⫾ 0.5
8.7 ⫾ 0.3
8.4 ⫾ 0.3
0.34 ⫾ 0.03
0.38 ⫾ 0.01
0.40 ⫾ 0.02
0.25 ⫾ 0.02
0.29 ⫾ 0.01
0.32 ⫾ 0.02
(59)
(232)
(61)
6.3 ⫾ 0.4bb
8.7 ⫾ 0.2
9.5 ⫾ 0.6
0.27 ⫾ 0.02bb
0.39 ⫾ 0.01
0.48 ⫾ 0.03d
0.20 ⫾ 0.01bb
0.30 ⫾ 0.01
0.39 ⫾ 0.03a
Data are presented as mean ⫾ SE. Statistical analyses were performed after log-transformation. The significance of the highest tertile values
was the comparison with the middle and lowest tertile values, and that of the lowest tertile values was the comparison with the middle tertile
values.
a
P ⬍ 0.005.
b
P ⬍ 0.001.
c
P ⬍ 0.01.
d
P ⬍ 0.02.
e
P ⬍ 0.002.
the females in the study. Plasma adiponectin levels were
inversely correlated with serum TG (r ⫽ ⫺0.33, P ⬍ 0.0001),
atherogenic index (r ⫽ ⫺0.34, P ⬍ 0.0001), apo B (r ⫽ ⫺0.45,
P ⬍ 0.0001), or E (r ⫽ ⫺0.29, P ⬍ 0.05), and these correlations
became stronger after adjusting for BMI or BFM. Adiponectin
levels were positively correlated with serum HDL-C (r ⫽
0.39, P ⬍ 0.0001) and apo A-I (r ⫽ 0.42, P ⬍ 0.002), and similar
trends were observed after adjustment for BMI or BFM.
Changes in the relationship between adiponectin and diastolic BP, uric acid, or LDL-C were slightly significant after
adjusting for BMI or BFM, and the correlations between
adiponectin and age, creatinine, or BUN became weaker after
the adjustment (Table 2).
The mean plasma adiponectin concentration was lower,
not only in the highest tertile of TG than in the middle or
lowest tertile of TG (5.9 ⫾ 0.5 vs. 7.5 ⫾ 0.3, 9.2 ⫾ 0.2 ␮g/ml;
P ⬍ 0.005, 0.001), but also in the lowest tertile of HDL-C than
in the middle or highest tertile of HDL-C (5.7 ⫾ 0.5 vs. 7.8 ⫾
0.2, 10.1 ⫾ 0.4 ␮g/ml; both P ⬍ 0.001). The differences remained significant after adjustment for BMI or BFM (Table
3). Although adiponectin levels in the high-atherogenic index before and after adjustment for BMI or BFM were also
lower than in the other subjects (all P ⬍ 0.001), serum TC and
LDL-C levels did not affect plasma adiponectin concentrations. In two-way ANOVA, despite adjusting for stratified
BMI, age, or diastolic BP, plasma adiponectin concentrations
decreased in females with the highest tertiles of TG (Fig. 1)
or the lowest tertiles of HDL-C (Fig. 2).
Discussion
Although the total physiological role of adiponectin is as
yet unclear, experimental studies have indicated that adi-
ponectin has potential antiatherogenic and antiinflammatory
properties (7–10). At the early stages of atherosclerosis, endothelial cell activation by various inflammatory stimuli,
including TNF␣, results in the synthesis of adhesion molecules and increases the adherence of monocytes. This monocyte adhesion to the arterial endothelium is considered crucial for the development of vascular diseases (3, 5–10).
Adiponectin has been shown to inhibit both the production
and action of TNF␣, a cytokine that has direct effects on the
adhesion molecules (7–10).
Hotta et al. (15) reported that the significant negative
correlation is observed between adiponectin and TG levels, and positive correlation between adiponectin and
HDL-C levels in type 2 diabetes. The present results extend
this finding by demonstrating that plasma adiponectin
concentrations are not only inversely correlated to TG,
atherogenic index, apo B, and apo E, but also positively
correlated to serum HDL-C and apo A-I in nondiabetic
female subjects. We also found that the mean plasma adiponectin concentration before and after adjustment for
BMI or BFM was decreased in high-TGnemia, high-atherogenic index, and low-HDL-Cnemia. These declines were
also observed after adjusting for age or diastolic BP. Because adiponectin acts to reduce atherogenic reaction (7–
10), these data have been interpreted to indicate that hypoadiponectinemia in dyslipidemia accelerates the
atherogenic reaction. The mechanism underlying the observed close association between plasma adiponectin and
dyslipidemia is presently unknown. This may be attributable to insulin resistance and/or hyperinsulinemia (22,
23). Yamauchi et al. (23) reported that adiponectin administration leads to decreased muscle and liver TG content,
Matsubara et al. • Decreased Adiponectin in Dyslipidemia
J Clin Endocrinol Metab, June 2002, 87(6):2764 –2769 2767
FIG. 1. BMI (A), age (B), or diastolic BP
(C)-adjusted plasma adiponectin concentrations by tertiles of serum TG levels. Data are presented as mean ⫾ SE.
increasing combustion of FFA in obese and diabetic mice.
Therefore, adiponectin reverses insulin resistance in obese
and diabetic mice (23). Recent genomic scan studies (24,
25) have revealed linkage of the metabolic syndrome and/or diabetes to a region on chromosome 3
(3q26 –27), where the gene encoding adiponectin, apM1, is
located (26).
The weak positive correlations between adiponectin and
age, BUN, or creatinine levels became lower after adjusting
for BMI or BFM. Changes of these correlations before and
after adjusting for body composition may suggest the possible effect of these factors on plasma adiponectin metabolism. The changing level of adiponectin concentration in
postmenopausal aged women may suggest an interaction
2768
J Clin Endocrinol Metab, June 2002, 87(6):2764 –2769
Matsubara et al. • Decreased Adiponectin in Dyslipidemia
FIG. 2. BMI (A), age (B), or diastolic BP
(C)-adjusted plasma adiponectin concentrations by tertiles of serum HDL-C levels. Data are presented as mean ⫾ SE.
with sex hormones. Furthermore, we demonstrated that apo
A-I, B, and E were associated with adiponectin levels, suggesting the possibility of association with serum TG and
HDL-C.
This study was undertaken to test the hypothesis that
adiponectin was associated with lipid metabolism, independent of adiposity. Our results provide evidence in favor of
this hypothesis and further suggest that adiponectin may
affect these lipid risk factors for atherosclerosis, separate
from the known risk attributable to adiposity (16 –19).
In conclusion, we demonstrated significant correlations
between adiponectin and adverse changes in such lipids as
serum TG, HDL-C, atherogenic index, and apo A-I, B, and E
levels, before and after adjusting for body mass and composition. If decreased plasma adiponectin concentration can
be shown to cause these adverse lipid changes, this adipo-
Matsubara et al. • Decreased Adiponectin in Dyslipidemia
cytokine might be directly involved in promoting the atherosclerotic changes seen in the metabolic syndrome.
Acknowledgments
Received August 28, 2001. Accepted February 14, 2002.
Address all correspondence and requests for reprints to: Miyao Matsubara, M.D., Division of Endocrinology and Metabolism, Internal Medicine, Otaru City General Hospital, Wakamatsu 1-2-1, Otaru 047-8550,
Japan. E-mail: [email protected].
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