(Circulation. 2001;103:1057.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages
From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan, and the Cellular Technology Institute (M.M., Y. Ohmoto), Otsuka Pharmaceutical Co., Ltd, Tokushima, Japan.
Correspondence to Noriyuki Ouchi, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan. E-mail ouchi{at}imed2.med.osaka-u.ac.jp
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Abstract |
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Background—Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages.
Methods and Results—Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry.
Conclusions—The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.
Key Words: atherosclerosis • macrophages • receptors • adiponectin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Obesity is the most common risk factor for cardiovascular morbidity and mortality.1 2 3 Adipose tissue is not simply an energy storage organ, but also a secretory organ, producing a variety of bioactive substances, including leptin, tumor necrosis factor-
, plasminogen activator inhibitor type
1, and adiponectin, that may directly contribute to the development of
vascular
diseases.4 5 6 7 8 9
Adiponectin is an adipocyte-specific plasma protein homologous to
collagen VIII, collagen X, and complement factor
C1q,10 and it is abundantly
present in human plasma, accounting for 0.01% of the total plasma
protein.11 Plasma
adiponectin levels are reduced in patients with coronary artery
disease, including myocardial
infarction.9 We recently
demonstrated that plasma adiponectin accumulated in the subendothelial
space in the rat injured carotid artery model and that adiponectin
inhibited tumor necrosis factor-–induced expression of adhesion
molecules in vascular endothelial
cells.9 12
Therefore, the decrease in the plasma adiponectin may directly
correlate with the development of vascular diseases as an
adipocyte-derived endocrine modulator for proinflammatory stimuli when
the endothelial barrier is injured. In the early stages of atherosclerosis, the circulating monocytes attach to injured endothelial cells and infiltrate the subendothelial space, leading to differentiation into macrophages.13 14 15 16 Subsequently, the macrophages take up modified LDL and transform into foam cells by accumulating intracellular cholesterol.13 14 15 16 The accumulation of lipid-laden foam cells and the ongoing macrophage-related inflammation are key features in early atherosclerotic lesions.14 15 16 The scavenger receptor family proteins, such as class A macrophage scavenger receptor (MSR) and class B MSR (CD36), play a major role in lipid accumulation and the foam cell formation of macrophages by taking up modified LDL.17 18 19 20 However, the endogenous regulator of MSR has not been fully elucidated. In this study, we investigated the effects of the adipocyte-derived plasma protein adiponectin on lipid accumulation and class A MSR expression in human monocyte-derived macrophages.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Cell Culture
Mononuclear cells were isolated from peripheral blood by density gradient centrifugation, as previously described.21 The cells were suspended in RPMI-1640 (Gibco) supplemented with 10% human type AB serum and incubated for 1 hour at 37°C in cell culture dishes. Nonadherent cells were removed by washing twice with PBS. The remaining adherent cells were cultured in the same medium. After 7 days of incubation, the cells were used as human monocyte-derived macrophages. The medium was replaced every 2 or 3 days. Human monocyte-derived macrophages were cultured in the medium for 7 days and then incubated with the indicated amount of adiponectin in the same medium for the times indicated. Human recombinant adiponectin was prepared as previously described.11
Analysis of Cellular Cholesteryl Ester Contents
and Lipid Accumulation
Human monocyte-derived macrophages were treated with
or without 30 µg/mL adiponectin for 3 days. The cellular cholesterol
content was determined by the enzymatic, fluorometric method, as
previously described.22
Briefly, the cellular lipids were extracted with hexane/isopropanol
(3/2, v/v), dried under a nitrogen flush, and then dissolved in
isopropanol as previously
described.23 For the
determination of free cholesterol, the supernatant was added to enzyme
mixtures containing cholesterol oxidase (0.16 IU/mL). For the
evaluation of total cholesterol, the supernatant was added to enzyme
mixtures containing both cholesterol oxidase (0.16 IU/mL) and
cholesterol esterase (60 U/mL). The reaction mixtures for measuring
free cholesterol and those for measuring total cholesterol were
incubated at 37°C for 1 hour and 2 hours, respectively, followed by
the addition of sodium hydroxide to terminate the reaction. Fluorescent
intensity was measured with excitation at 310 nm and emission at 407
nm. The mass of cholesteryl ester was calculated by subtracting free
cholesterol from total cholesterol. After lipid extraction, the
cellular protein was dissolved in sodium hydroxide, and the protein
concentration was determined by the method of Lowry et
al.24 For detecting lipids
accumulated in macrophages, oil red O staining was performed as
previously described.25 For
detection of adiponectin on macrophages, anti-adiponectin monoclonal
antibodies (ANOC 9108) were used as previously
reported.12
Immunoblot Analysis
Human monocyte-derived macrophages were treated with
or without 30 µg/mL adiponectin for 2 days. Whole cell lysates were
resolved on 7.5% SDS-polyacrylamide gels, followed by electrophoretic
transfer to nitrocellulose membranes (Amersham). The membranes were
exposed to mouse monoclonal anti-human class A MSR primary antibodies
(a gift from Dr. Motohiro Takeya, Kumamoto University) and then exposed
to anti-mouse secondary antibodies conjugated with horseradish
peroxidase. The antibody was detected by Phototope-HRP Western
Detection Kit (New England Biolabs).
Immunofluorescent Flow Cytometry
To detect the cell-surface expression of CD36,
immunofluorescence flow cytometric analysis was performed using
FITC-conjugated mouse monoclonal antibodies against human CD36 (OKM-5,
Ortho Diagnostic System). Human monocyte-derived macrophages were
treated with or without 30 µg/mL adiponectin for 2 days. The cells
were washed with PBS and incubated with FITC-conjugated mouse
anti-human CD36 antibodies (OKM5) or FITC-conjugated control mouse IgG
for 30 minutes on ice. The cells were analyzed using a FACScan flow
cytometer (Becton Dickinson). Data were analyzed with the Cell Quest
program.
Northern Blot Analysis
Human monocyte-derived macrophages were treated with
the indicated concentrations of adiponectin for 2 days. Total cellular
RNA was prepared by RNA-TRIZOL extraction (Gibco). Total RNA (10 µg
per lane) was electrophoresed and transferred to a nylon membrane.
Human class A MSR cDNA (1350 bp, nucleotides 1 to 1350 in the human
class A MSR cDNA sequence) was kindly provided by Dr Tatsuhiko Kodama
(Tokyo University).18 Human
full-length lipoprotein lipase (LPL) or apolipoprotein E (apoE) cDNA
was amplified by reverse transcriptase polymerase chain reaction,
subcloned into pBluescript KS (TOYOBO), and used as a cDNA probe. The
membranes were hybridized with human class A MSR, LPL, or apoE cDNA
probes labeled with [-32P]dCTP by means
of a random primer labeling system (Amersham). Hybridized membranes
were exposed to Kodak XAR-5 film between 2 intensifying
screens.
Cell Transfection and Measurement of
Luciferase Activity
Class A MSR promoter fragment (from -630 to +50 bp)
was kindly provided by Dr Akiyo Matsumoto (National Institute of Health
and Nutrition, Tokyo, Japan). The promoter fragment was subcloned into
the luciferase reporter vector with pGL3-Basic (Promega). For the
transfection study, a human monocytic cell line (THP-1 cells; Japanese
Cancer Research Resources Bank) was used. THP-1 cells were transfected
using the DEAE-dextran sulfate
method,26 as follows:
2x107 cells were cotransfected with 20 µg
of class A MSR pGL3 plasmid and 1 µg of SV40 control plasmid
(Promega) in 250 µg of DEAE-dextran for 60 minutes and shocked with
10% DMSO for 2 minutes. After transfection, the cells were incubated
with RPMI-1640 supplemented with 10% fetal calf serum for 24 hours and
then treated with phorbol 12-myristate 13-acetate at a final
concentration of 50 ng/mL for 24 hours to differentiate monocytes from
macrophage-like cells. THP-1 macrophages were treated with or without
30 µg/mL adiponectin for 24 hours. Luciferase activity was measured
using a dual luciferase assay kit and a
luminometer.
AcLDL Binding and Uptake
Macrophage binding and uptake of acetylated LDL
(AcLDL) were analyzed by flow cytometry using lipoproteins labeled with
the fluorescent probe 1,1'-dioctadecyl-1 to
3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). DiI-AcLDL and
unlabeled AcLDL were purchased from Biomedical Technologies. After
treatment with the indicated concentrations of adiponectin for 2 days,
the cells were incubated with varying concentrations of DiI-AcLDL
dissolved in RPMI-1640 containing 2% lipoprotein-deficient human
serum. Cells were incubated at 4°C for 30 minutes for binding assays
and at 37°C for 3 hours for uptake experiments. For competition
assays, unlabeled AcLDL in excess amounts (50-fold) were added with
DiI-AcLDL. The cells were resuspended in PBS and analyzed using a
FACScan flow cytometer (Becton Dickinson). Data were analyzed by the
Cell Quest program. Specific fluorescent intensity was calculated by
subtracting autofluorescent intensity from the mean fluorescent
intensity of DiI-labeled cells.
Immunohistochemical Staining
Human abdominal aorta was obtained from a human
subject who underwent an operation for an abdominal aortic aneurysm,
and the aorta was then embedded in paraffin. Adiponectin
immunohistochemical staining was performed using anti-adiponectin
monoclonal antibodies (ANOC 9108), as previously
described.12 Macrophages
were detected using anti-CD68 antibody (DAKO), as previously
described.25 This subject
gave written informed consent. The Ethics Committee of Osaka University
approved the study.
Statistic Analysis
Data are presented as mean±SD. Differences were
analyzed by Student’s unpaired
t test or 1-way ANOVA.
P<0.05 was considered
statistically significant.
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Results |
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Adiponectin Reduces Cholesteryl Ester Contents and Lipid Droplets in Human Monocyte- Derived Macrophages
We first investigated the effects of adiponectin on cholesteryl ester accumulation in human monocyte-derived macrophages. Treatment of macrophages with physiological concentrations of adiponectin (30 µg/mL) for 3 days significantly reduced cholesteryl ester contents by
50% compared with untreated controls
(Figure 1
). Double staining of the macrophages with
anti-adiponectin antibody and oil red O was performed. The
adiponectin-treated macrophages contained fewer lipid droplets and
appeared more elongated than the untreated macrophages
(Figure 2). Adiponectin was detected only on the
adiponectin-treated macrophages and not on the untreated macrophages.
These results indicated that adiponectin suppressed the
macrophage-to-foam cell transformation in vitro.
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Adiponectin Suppresses the Expression of Class
A MSR Without Affecting that of CD36
The scavenger receptor family proteins play an
important role in lipid accumulation and the foam cell formation of
macrophages. Therefore, we next investigated whether adiponectin could
modulate the expression of 2 major scavenger receptors, class A MSR and
CD36, in human monocyte-derived macrophages. The immunoblot analysis
revealed that the major isoform of class A MSR was type I protein in
human monocyte-derived macrophages. Treatment of human macrophages with
adiponectin (30 µg/mL) for 2 days markedly suppressed the expression
of class A MSR proteins
(Figure 3A). Cotreatment of the anti-adiponectin monoclonal
antibody ANOC 9104 with adiponectin reversed the adiponectin-induced
suppression of class A MSR protein expression
(Figure 3B). In contrast to class A MSR, adiponectin
treatment (30 µg/mL) had no effect on CD36 protein levels by flow
cytometric analysis
(Figure 4). The effects of adiponectin on class A MSR
steady-state mRNA levels and promoter activity were further examined by
Northern blot and luciferase assay, respectively. Human
monocyte-derived macrophages expressed type I and II class A MSR mRNAs
(Figure 5). Adiponectin treatment suppressed both type I and
II class A MSR mRNA levels in a dose-dependent manner
(Figure 5). The promoter activity of class A MSR standardized
by SV40 promoter was significantly reduced by adiponectin treatment in
the transfected human monocytic cell line of THP-1-derived macrophages
(Figure 6). These results indicated that adiponectin
decreased the class A MSR expression at the transcriptional
level.
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Adiponectin Reduces Binding and Uptake of
DiI-AcLDL
The function of class A MSR was examined by flow
cytometric analysis using DiI-AcLDL. After treatment with or without 30
µg/mL of adiponectin for 2 days, cells were incubated with varying
concentrations of Dil-AcLDL for 30 minutes at 4°C. Adiponectin
treatment reduced the specific and saturable binding of Dil-AcLDL to
human monocyte-derived macrophages compared with untreated control
(Figure 7A), and the suppressive effects of adiponectin on
DiI-AcLDL binding were observed in a dose-dependent manner
(Figure 7B). Adiponectin treatment did not affect nonspecific
binding in the presence of excess unlabeled AcLDL
(Figure 7A). Additionally, the binding of Dil-AcLDL to
macrophages was not suppressed when adiponectin was added at the same
time as Dil-AcLDL (data not shown), suggesting that adiponectin does
not occupy the binding sites of Dil-AcLDL to macrophages. Uptake of
DiI-AcLDL by human macrophages was further analyzed by flow cytometry.
Cells treated with the indicated concentrations of adiponectin for 2
days were incubated with 5 µg/mL Dil-AcLDL for 3 hours at 37°C.
Adiponectin treatment dose-dependently reduced Dil-AcLDL uptake in
human macrophages
(Figures 8A and 8B). Treatment with 30 µg/mL adiponectin
resulted in a 40% reduction of Dil-AcLDL uptake
(Figure 8B). The inhibitory effect of adiponectin on
Dil-AcLDL uptake was partially but significantly reversed by
cotreatment with the anti-adiponectin monoclonal antibody ANOC 9104
(Figure 8C). These findings indicated that adiponectin
suppressed class A MSR function in human monocyte-derived
macrophages.
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Effect of Adiponectin on LPL, ApoE, and Class A
MSR mRNA Levels
We next investigated whether adiponectin could modulate
macrophage differentiation. Because LPL and apoE are well-characterized
markers of macrophage differentiation, the effects of adiponectin on
LPL, apoE, and class A MSR mRNA levels were analyzed by Northern
blotting. Adiponectin treatment reduced the steady-state mRNA levels of
LPL and class A MSR without affecting those of apoE
(Figure 9).
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Expression of Adiponectin in Human Injured
Vascular Wall
Finally, we examined the localization of adiponectin in
the lesions of the human injured aorta by immunohistochemical analysis.
Double immunostaining of adiponectin and macrophages revealed that
adiponectin was abundant in the endothelium and in the subendothelial
space, which also contains macrophages; the endothelial injury was
confirmed by thrombus attachment
(Figure 10). However, adiponectin was not detected in the
subendothelial space of atherosclerotic lesions with an intact
endothelium (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we demonstrated that physiological concentrations of adiponectin (3 to 30 µg/mL) had significant inhibitory effects on lipid accumulation, class A MSR expression, and class A MSR ligand binding and uptake activities in human monocyte-derived macrophages in vitro.
The generation of lipid-laden foam cells is considered a key step in the pathogenesis of atherosclerosis.13 14 15 16 Class A MSRs play a pivotal role in foam cell formation from macrophages by mediating the uptake of modified LDL.17 18 We and others have demonstrated by immunohistochemical analyses that class A MSR protein is detected in the macrophages from human atherosclerotic lesions.18 25 27 Recent studies showed that certain double-knockout mice (class A MSR/apoE) had smaller atherosclerotic lesions than single-knockout mice (apoE).28 These findings indicate that class A MSRs contribute to the generation of atherosclerotic lesions. Therefore, our present observations suggest that adiponectin may act as a negative endocrine modulator for foam cell formation through the inhibition of class A MSR expression.
The regulation of the scavenger receptor family proteins is
poorly understood, although it plays an important role in the
development of atherosclerosis. The expression of class A MSR and CD36
increased during monocyte-to-macrophage
differentiation.21 29
However, a recent study showed that the expression of these 2 proteins
was differentially regulated by the nuclear receptor
pathways.30 Although CD36 is
positively regulated by the nuclear receptor peroxisome
proliferator-activated receptor
,30 the nuclear receptor
related to the regulation of class A MSR has not been well
characterized. In the current study, adiponectin specifically decreased
the protein levels of class A MSR without altering those of CD36. In
addition, adiponectin decreased the steady-state mRNA levels of class A
MSR and LPL mRNA without altering those of apoE. Because class A MSR,
LPL, and apoE reportedly increase during monocyte-to-macrophage
differentiation,29 31 32
adiponectin may partially modulate macrophage differentiation and
affect lipid accumulation in the macrophages. The promoter assay of
class A MSR revealed that adiponectin suppressed the class A MSR
expression at the transcriptional level, although further studies are
needed to clarify the precise transcriptional regulatory mechanism by
which adiponectin decreases the class A MSR expression.
Recently, we detected adiponectin in the rat catheter-injured vascular walls but not in the intact vascular walls.12 In addition, adiponectin accumulated in the subendothelial space of the vascular wall from the plasma at an early phase of catheter injury. In the present study, adiponectin was detected around macrophages in the human injured aorta where a thrombus was attached. These observations suggest that adiponectin may rapidly accumulate in the vascular wall when the endothelial barrier is injured and modulate the macrophage-to-foam cell transformation in vivo.
In summary, we demonstrated that adiponectin reduced lipid accumulation in human monocyte-derived macrophages through an inhibition of class A MSR expression. Our findings suggest that the adipocyte-specific plasma protein adiponectin is not only a negative regulator of the endothelial adhesion molecule expression,9 but also a modulator for macrophage foam cell formation, thus providing a fundamental mechanism for the link between overnutrition and atherosclerosis.
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Acknowledgments |
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This work was supported by grants from the Japanese Ministry of Education, the Japan Society for Promotion of Science-Research for the Future Program, and the Kato Memorial Trust for NAMBYO Research. The authors thank Dr T. Kodama for providing a human class A MSR cDNA probe, Dr M. Takeya for providing anti-human class A MSR antibodies, and Dr A. Matsumoto for providing a class A MSR promoter fragment.
Received August 24, 2000; revision received October 17, 2000; accepted October 27, 2000.
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G. Maiolino, M. Cesari, D. Sticchi, M. Zanchetta, L. Pedon, K. Antezza, A. C. Pessina, and G. P. Rossi Plasma Adiponectin for Prediction of Cardiovascular Events and Mortality in High-Risk Patients J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3333 - 3340. [Abstract] [Full Text] [PDF]
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A. Qasim, N. N. Mehta, M. G. Tadesse, M. L. Wolfe, T. Rhodes, C. Girman, and M. P. Reilly Adipokines, insulin resistance, and coronary artery calcification. J. Am. Coll. Cardiol., July 15, 2008; 52(3): 231 - 236. [Abstract] [Full Text] [PDF]
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C. Natal, P. Restituto, C. Inigo, I. Colina, J. Diez, and N. Varo The Proinflammatory Mediator CD40 Ligand Is Increased in the Metabolic Syndrome and Modulated by Adiponectin J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2319 - 2327. [Abstract] [Full Text] [PDF]
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R Olufadi and C D Byrne Clinical and laboratory diagnosis of the metabolic syndrome J. Clin. Pathol., June 1, 2008; 61(6): 697 - 706. [Abstract] [Full Text] [PDF]
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E. Galluccio, P. Piatti, L. Citterio, P. C. G. Lucotti, E. Setola, L. Cassina, M. Oldani, I. Zavaroni, E. Bosi, A. Colombo, et al. Hyperinsulinemia and impaired leptin-adiponectin ratio associate with endothelial nitric oxide synthase polymorphisms in subjects with in-stent restenosis Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E978 - E986. [Abstract] [Full Text] [PDF]
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J Polak, Z Kovacova, C Holst, C Verdich, A Astrup, E Blaak, K Patel, J M Oppert, D Langin, J A Martinez, et al. Total adiponectin and adiponectin multimeric complexes in relation to weight loss-induced improvements in insulin sensitivity in obese women: the NUGENOB study. Eur. J. Endocrinol., April 1, 2008; 158(4): 533 - 541. [Abstract] [Full Text] [PDF]
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N. Cheurfa, D. Dubois-Laforgue, D. A.F. Ferrarezi, A. F. Reis, G. M. Brenner, C. Bouche, C. Le Feuvre, F. Fumeron, J. Timsit, M. Marre, et al. The Common -866G>A Variant in the Promoter of UCP2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men Diabetes, April 1, 2008; 57(4): 1063 - 1068. [Abstract] [Full Text] [PDF]
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Y. Tabara, H. Osawa, R. Kawamoto, R. Tachibana-Iimori, M. Yamamoto, J. Nakura, T. Miki, H. Makino, and K. Kohara Reduced High-Molecular-Weight Adiponectin and Elevated High-Sensitivity C-Reactive Protein Are Synergistic Risk Factors for Metabolic Syndrome in a Large-Scale Middle-Aged to Elderly Population: the Shimanami Health Promoting Program Study J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 715 - 722. [Abstract] [Full Text] [PDF]
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K. Ohashi, H. Iwatani, S. Kihara, Y. Nakagawa, N. Komura, K. Fujita, N. Maeda, M. Nishida, F. Katsube, I. Shimomura, et al. Exacerbation of Albuminuria and Renal Fibrosis in Subtotal Renal Ablation Model of Adiponectin-Knockout Mice Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1910 - 1917. [Abstract] [Full Text] [PDF]
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A. E Schutte, H. W Huisman, R. Schutte, L. Malan, J. M van Rooyen, N. T Malan, and P. E H Schwarz Differences and similarities regarding adiponectin investigated in African and Caucasian women Eur. J. Endocrinol., August 1, 2007; 157(2): 181 - 188. [Abstract] [Full Text] [PDF]
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L. J. Moran, M. Noakes, P. M. Clifton, G. A. Wittert, D. P. Belobrajdic, and R. J. Norman C-Reactive Protein before and after Weight Loss in Overweight Women with and without Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 2944 - 2951. [Abstract] [Full Text] [PDF]
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D.C.Y. Yeung, A. Xu, C.W.S. Cheung, N.M.S. Wat, M.H. Yau, C.H.Y. Fong, M.T. Chau, and K.S.L. Lam Serum Adipocyte Fatty Acid-Binding Protein Levels Were Independently Associated With Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1796 - 1802. [Abstract] [Full Text] [PDF]
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H. Katagiri, T. Yamada, and Y. Oka Adiposity and Cardiovascular Disorders: Disturbance of the Regulatory System Consisting of Humoral and Neuronal Signals Circ. Res., July 6, 2007; 101(1): 27 - 39. [Abstract] [Full Text] [PDF]
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G. Fantuzzi and T. Mazzone Adipose Tissue and Atherosclerosis: Exploring the Connection Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 996 - 1003. [Abstract] [Full Text] [PDF]
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T. A. Hopkins, N. Ouchi, R. Shibata, and K. Walsh Adiponectin actions in the cardiovascular system Cardiovasc Res, April 1, 2007; 74(1): 11 - 18. [Abstract] [Full Text] [PDF]
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M. Bjursell, A. Ahnmark, M. Bohlooly-Y, L. William-Olsson, M. Rhedin, X.-R. Peng, K. Ploj, A.-K. Gerdin, G. Arnerup, A. Elmgren, et al. Opposing Effects of Adiponectin Receptors 1 and 2 on Energy Metabolism Diabetes, March 1, 2007; 56(3): 583 - 593. [Abstract] [Full Text] [PDF]
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W. Koenig, N. Khuseyinova, J. Baumert, C. Meisinger, and H. Lowel Serum Concentrations of Adiponectin and Risk of Type 2 Diabetes Mellitus and Coronary Heart Disease in Apparently Healthy Middle-Aged Men: Results From the 18-Year Follow-Up of a Large Cohort From Southern Germany J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1369 - 1377. [Abstract] [Full Text] [PDF]
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E. Cavusoglu, C. Ruwende, V. Chopra, S. Yanamadala, C. Eng, L. T. Clark, D. J. Pinsky, and J. D. Marmur Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain Eur. Heart J., October 1, 2006; 27(19): 2300 - 2309. [Abstract] [Full Text] [PDF]
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T. Soccio, Y.-Y. Zhang, S. Bacci, W. Mlynarski, G. Placha, G. Raggio, R. Di Paola, A. Marucci, M. T. Johnstone, E. V. Gervino, et al. Common Haplotypes at the Adiponectin Receptor 1 (ADIPOR1) Locus Are Associated With Increased Risk of Coronary Artery Disease in Type 2 Diabetes. Diabetes, October 1, 2006; 55(10): 2763 - 2770. [Abstract] [Full Text] [PDF]
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M. Bajaj and O. Ben-Yehuda A Big Fat Wedding: Association of Adiponectin With Coronary Vascular Lesions J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1163 - 1165. [Full Text] [PDF]
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F. Otsuka, S. Sugiyama, S. Kojima, H. Maruyoshi, T. Funahashi, K. Matsui, T. Sakamoto, M. Yoshimura, K. Kimura, S. Umemura, et al. Plasma Adiponectin Levels Are Associated With Coronary Lesion Complexity in Men With Coronary Artery Disease J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1155 - 1162. [Abstract] [Full Text] [PDF]
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C. Herder, H. Hauner, B. Haastert, K. Rohrig, W. Koenig, H. Kolb, S. Muller-Scholze, B. Thorand, R. Holle, and W. Rathmann Hypoadiponectinemia and Proinflammatory State: Two Sides of the Same Coin?: Results From the Cooperative Health Research in the Region of Augsburg Survey 4 (KORA S4) Diabetes Care, July 1, 2006; 29(7): 1626 - 1631. [Abstract] [Full Text] [PDF]
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Y. Aso, R. Yamamoto, S. Wakabayashi, T. Uchida, K. Takayanagi, K. Takebayashi, T. Okuno, T. Inoue, K. Node, T. Tobe, et al. Comparison of Serum High-Molecular Weight (HMW) Adiponectin With Total Adiponectin Concentrations in Type 2 Diabetic Patients With Coronary Artery Disease Using a Novel Enzyme-Linked Immunosorbent Assay to Detect HMW Adiponectin. Diabetes, July 1, 2006; 55(7): 1954 - 1960. [Abstract] [Full Text] [PDF]
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Y. Wang, K. S. L. Lam, L. Chan, K. W. Chan, J. B. B. Lam, M. C. Lam, R. C. L. Hoo, W. W. N. Mak, G. J. S. Cooper, and A. Xu Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex J. Biol. Chem., June 16, 2006; 281(24): 16391 - 16400. [Abstract] [Full Text] [PDF]
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K. Hara, M. Horikoshi, T. Yamauchi, H. Yago, O. Miyazaki, H. Ebinuma, Y. Imai, R. Nagai, and T. Kadowaki Measurement of the High-Molecular Weight Form of Adiponectin in Plasma Is Useful for the Prediction of Insulin Resistance and Metabolic Syndrome. Diabetes Care, June 1, 2006; 29(6): 1357 - 1362. [Abstract] [Full Text] [PDF]
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N. Bansal, V. Charlton-Menys, P. Pemberton, P. McElduff, J. Oldroyd, A. Vyas, A. Koudsi, P. E. Clayton, J. K. Cruickshank, and P. N. Durrington Adiponectin in Umbilical Cord Blood Is Inversely Related to Low-Density Lipoprotein Cholesterol But Not Ethnicity J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2244 - 2249. [Abstract] [Full Text] [PDF]
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R. Ouedraogo, X. Wu, S.-Q. Xu, L. Fuchsel, H. Motoshima, K. Mahadev, K. Hough, R. Scalia, and B. J. Goldstein Adiponectin Suppression of High-Glucose-Induced Reactive Oxygen Species in Vascular Endothelial Cells: Evidence for Involvement of a cAMP Signaling Pathway Diabetes, June 1, 2006; 55(6): 1840 - 1846. [Abstract] [Full Text] [PDF]
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J. Lo, S. E. Dolan, J. R. Kanter, L. C. Hemphill, J. M. Connelly, R. S. Lees, and S. K. Grinspoon Effects of Obesity, Body Composition, and Adiponectin on Carotid Intima-Media Thickness in Healthy Women J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1677 - 1682. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways Physiol Rev, April 1, 2006; 86(2): 515 - 581. [Abstract] [Full Text] [PDF]
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A. Ehling, A. Schaffler, H. Herfarth, I. H. Tarner, S. Anders, O. Distler, G. Paul, J. Distler, S. Gay, J. Scholmerich, et al. The Potential of Adiponectin in Driving Arthritis J. Immunol., April 1, 2006; 176(7): 4468 - 4478. [Abstract] [Full Text] [PDF]
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K. Matsushita, H. Yatsuya, K. Tamakoshi, K. Wada, R. Otsuka, S. Takefuji, K. Sugiura, T. Kondo, T. Murohara, and H. Toyoshima Comparison of Circulating Adiponectin and Proinflammatory Markers Regarding Their Association With Metabolic Syndrome in Japanese Men Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 871 - 876. [Abstract] [Full Text] [PDF]
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C. Kobashi, M. Urakaze, M. Kishida, E. Kibayashi, H. Kobayashi, S. Kihara, T. Funahashi, M. Takata, R. Temaru, A. Sato, et al. Adiponectin Inhibits Endothelial Synthesis of Interleukin-8 Circ. Res., December 9, 2005; 97(12): 1245 - 1252. [Abstract] [Full Text] [PDF]
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A. Singhal, N. Jamieson, M. Fewtrell, J. Deanfield, A. Lucas, and N. Sattar Adiponectin Predicts Insulin Resistance But Not Endothelial Function in Young, Healthy Adolescents J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4615 - 4621. [Abstract] [Full Text] [PDF]
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S. Pilz, R. Horejsi, R. Moller, G. Almer, H. Scharnagl, T. Stojakovic, R. Dimitrova, G. Weihrauch, M. Borkenstein, W. Maerz, et al. Early Atherosclerosis in Obese Juveniles Is Associated with Low Serum Levels of Adiponectin J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4792 - 4796. [Abstract] [Full Text] [PDF]
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A. Xu, K. W. Chan, R. L. C. Hoo, Y. Wang, K. C. B. Tan, J. Zhang, B. Chen, M. C. Lam, C. Tse, G. J. S. Cooper, et al. Testosterone Selectively Reduces the High Molecular Weight Form of Adiponectin by Inhibiting Its Secretion from Adipocytes J. Biol. Chem., May 6, 2005; 280(18): 18073 - 18080. [Abstract] [Full Text] [PDF]
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Y. Wang, K. S. L. Lam, J. Y. Xu, G. Lu, L. Y. Xu, G. J. S. Cooper, and A. Xu Adiponectin Inhibits Cell Proliferation by Interacting with Several Growth Factors in an Oligomerization-dependent Manner J. Biol. Chem., May 6, 2005; 280(18): 18341 - 18347. [Abstract] [Full Text] [PDF]
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T. Pischon, C. J Girman, N. Rifai, G. S Hotamisligil, and E. B Rimm Association between dietary factors and plasma adiponectin concentrations in men Am. J. Clinical Nutrition, April 1, 2005; 81(4): 780 - 786. [Abstract] [Full Text] [PDF]
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M.-P. Chen, J. C.-R. Tsai, F.-M. Chung, S.-S. Yang, L.-L. Hsing, S.-J. Shin, and Y.-J. Lee Hypoadiponectinemia Is Associated With Ischemic Cerebrovascular Disease Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 821 - 826. [Abstract] [Full Text] [PDF]
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M. I. Yilmaz, A. Sonmez, S. Kilic, T. Celik, N. Bingol, M. Pinar, T. Mumcuoglu, and M. Ozata The association of plasma adiponectin levels with hypertensive retinopathy Eur. J. Endocrinol., February 1, 2005; 152(2): 233 - 240. [Abstract] [Full Text] [PDF]
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M.-T. Berthier, A. Houde, M. Cote, A.-M. Paradis, P. Mauriege, J. Bergeron, D. Gaudet, J.-P. Despres, and M.-C. Vohl Impact of adiponectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men J. Lipid Res., February 1, 2005; 46(2): 237 - 244. [Abstract] [Full Text] [PDF]
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M. B. Schulze, I. Shai, E. B. Rimm, T. Li, N. Rifai, and F. B. Hu Adiponectin and Future Coronary Heart Disease Events Among Men With Type 2 Diabetes Diabetes, February 1, 2005; 54(2): 534 - 539. [Abstract] [Full Text] [PDF]
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H. Waki, T. Yamauchi, J. Kamon, S. Kita, Y. Ito, Y. Hada, S. Uchida, A. Tsuchida, S. Takekawa, and T. Kadowaki Generation of Globular Fragment of Adiponectin by Leukocyte Elastase Secreted by Monocytic Cell Line THP-1 Endocrinology, February 1, 2005; 146(2): 790 - 796. [Abstract] [Full Text] [PDF]
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S Kaser, A Moschen, A Cayon, A Kaser, J Crespo, F Pons-Romero, C F Ebenbichler, J R Patsch, and H Tilg Adiponectin and its receptors in non-alcoholic steatohepatitis Gut, January 1, 2005; 54(1): 117 - 121. [Abstract] [Full Text] [PDF]
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K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, M. H. Kang, T. H. Ahn, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients Circulation, December 14, 2004; 110(24): 3687 - 3692. [Abstract] [Full Text] [PDF]
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A. H. Berg, Y. Lin, M. P. Lisanti, and P. E. Scherer Adipocyte differentiation induces dynamic changes in NF-{kappa}B expression and activity Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1178 - E1188. [Abstract] [Full Text] [PDF]
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G. K. Shetty, P. A. Economides, E. S. Horton, C. S. Mantzoros, and A. Veves Circulating Adiponectin and Resistin Levels in Relation to Metabolic Factors, Inflammatory Markers, and Vascular Reactivity in Diabetic Patients and Subjects at Risk for Diabetes Diabetes Care, October 1, 2004; 27(10): 2450 - 2457. [Abstract] [Full Text] [PDF]
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M. Furuhashi, N. Ura, N. Moniwa, Y. Shinshi, H. Kouzu, M. Nishihara, N. Kokubu, T. Takahashi, K.-i. Sakamoto, M. Hayashi, et al. Possible Impairment of Transcardiac Utilization of Adiponectin in Patients With Type 2 Diabetes Diabetes Care, September 1, 2004; 27(9): 2217 - 2221. [Abstract] [Full Text] [PDF]
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H. Staiger, S. Kaltenbach, K. Staiger, N. Stefan, A. Fritsche, A. Guirguis, C. Peterfi, M. Weisser, F. Machicao, M. Stumvoll, et al. Expression of Adiponectin Receptor mRNA in Human Skeletal Muscle Cells Is Related to In Vivo Parameters of Glucose and Lipid Metabolism Diabetes, September 1, 2004; 53(9): 2195 - 2201. [Abstract] [Full Text] [PDF]
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U. Meier and A. M. Gressner Endocrine Regulation of Energy Metabolism: Review of Pathobiochemical and Clinical Chemical Aspects of Leptin, Ghrelin, Adiponectin, and Resistin Clin. Chem., September 1, 2004; 50(9): 1511 - 1525. [Abstract] [Full Text] [PDF]
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S. Bacci, C. Menzaghi, T. Ercolino, X. Ma, A. Rauseo, L. Salvemini, C. Vigna, R. Fanelli, U. Di Mario, A. Doria, et al. The +276 G/T Single Nucleotide Polymorphism of the Adiponectin Gene Is Associated With Coronary Artery Disease in Type 2 Diabetic Patients Diabetes Care, August 1, 2004; 27(8): 2015 - 2020. [Abstract] [Full Text] [PDF]
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