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(Circulation. 2000;102:1296.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-B Signaling Through a cAMP-Dependent Pathway

Noriyuki Ouchi, MD; Shinji Kihara, MD, PhD; Yukio Arita, MD; Yoshihisa Okamoto, MD; Kazuhisa Maeda, MD, PhD; Hiroshi Kuriyama, MD; Kikuko Hotta, MD, PhD; Makoto Nishida, MD; Masahiko Takahashi, MD, PhD; Masahiro Muraguchi, PhD; Yasukazu Ohmoto, PhD; Tadashi Nakamura, MD, PhD; Shizuya Yamashita, MD, PhD; Tohru Funahashi, MD, PhD; Yuji Matsuzawa, MD, PhD

From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and the Cellular Technology Institute, Otsuka Pharmaceutical Co, Ltd, Tokushima (M.M., Y. Ohmoto), Japan. The first 2 authors contributed equally to this work.

Correspondence to Noriyuki Ouchi, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2–2, Yamada-oka, Suita, Osaka, 565-0871, Japan. E-mail ouchi{at}imed2.med.osaka-u.ac.jp

	Abstract

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Background—Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor- (TNF-)–induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (Circulation. 1999;100:2473–2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin.

Methods and Results—The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 µg/mL of adiponectin, then exposed to TNF- (10 U/mL) or vehicle for the times indicated. NF-B–DNA binding activity was determined by electrophoretic mobility shift assays. TNF-–inducible phosphorylation signals were detected by immunoblotting. Adiponectin specifically bound to HAECs in a saturable manner and inhibited TNF-–induced mRNA expression of monocyte adhesion molecules without affecting the interaction between TNF- and its receptors. Adiponectin suppressed TNF-–induced IB- phosphorylation and subsequent NF-B activation without affecting other TNF-–mediated phosphorylation signals, including Jun N-terminal kinase, p38 kinase, and Akt kinase. This inhibitory effect of adiponectin is accompanied by cAMP accumulation and is blocked by either adenylate cyclase inhibitor or protein kinase A (PKA) inhibitor.

Conclusions—These observations raise the possibility that adiponectin, which is naturally present in the blood stream, modulates the inflammatory response of endothelial cells through cross talk between cAMP-PKA and NF-B signaling pathways.

Key Words: endothelium • atherosclerosis • NF-B • adiponectin

	Introduction

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Adipose tissue expresses various secretory proteins, including leptin, tumor necrosis factor- (TNF-), and plasminogen activator inhibitor type 1,^{1 2 3 4 5} which may contribute to the development of cardiovascular diseases.⁴ Although obesity, defined as excess body fat, is frequently accompanied by cardiovascular diseases,^{6 7 8} the molecular basis for the link between obesity and vascular disease has not yet been fully clarified. From an extensive search of the human adipose tissue cDNA library, we isolated an adipocyte-specific cDNA encoding a 244-amino-acid protein, adiponectin, that is homologous to collagen VIII and X and complement factor C1q.⁹ Adiponectin is the most abundant gene product in adipose tissue⁹ and accounts for 0.01% of total plasma protein.¹⁰ Plasma adiponectin level was decreased in obesity.¹⁰ We recently demonstrated that adiponectin inhibited TNF-–induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (CAD),¹¹ suggesting that, like other adipocyte-derived endocrine factors, adiponectin may directly relate to the development of vascular diseases. However, the molecular mechanism by which adiponectin inhibited TNF-–inducible adhesion molecule expression has not been clarified.

Endothelial cell activation by various inflammatory stimuli, including TNF-, increases the adherence of monocytes, which is considered a crucial step for the development of vascular diseases.¹² The expression of endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1), is considered to play a pivotal role in this monocyte adhesion to arterial endothelium.¹² The transcriptional factor nuclear transcription factor-B (NF-B) is an important factor involved in the transcriptional regulation of VCAM-1, E-selectin, and ICAM-1 stimulated by TNF-.¹³ We hypothesized that adiponectin might modulate endothelial functions through inhibition of the NF-B pathway.

In this study, we investigated the proposition that adiponectin suppressed TNF-–induced NF-B activation in human aortic endothelial cells (HAECs) via a cAMP-dependent pathway.

	Methods

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Cell Culture
HAECs (Clonetics) were maintained in 10-cm plastic plates precoated with type I collagen (Becton Dickinson) as previously described.¹¹ For experiments on TNF- induction, HAECs in a confluent state were preincubated for 18 hours in medium 199 (Gibco) containing 0.5% FCS and 3% BSA with the indicated amount of adiponectin, then exposed to human recombinant TNF- (R&D systems) or vehicle at a final concentration of 10 U/mL for the times indicated. Human recombinant adiponectin was prepared as previously described.¹⁰ Cells were pretreated for 1 hour with 200 µmol/L of the adenylate cyclase inhibitor dideoxyadenosine (ddAdo) (Calbiochem), 10 µmol/L of the protein kinase A (PKA) inhibitor R-p-cAMP (Rp-cAMP) (Calbiochem), or vehicle.

Association of Adiponectin With HAECs
Recombinant adiponectin was biotinylated with NHS-LC-Biotin (Pierce). HAECs (5x10⁴ cells/well in 96-well plates) were incubated with the indicated amount of biotinylated adiponectin for 1 hour at 37°C. Cell-surface association of biotinylated adiponectin was quantified by ELISA with streptavidin-conjugated horseradish peroxidase (HRP) and o-phenylenediamine dihydrochloride. The absorbance was measured at 492 nm. The data were represented by subtracting the amount of association in the presence of 100-fold excess unlabeled adiponectin from the total association.

TNF- Binding Assay
HAECs (2x10⁵ cells/well in 24-well plates) were incubated for 18 hours with the indicated amount of adiponectin in medium 199 containing 0.5% FCS and 3% BSA. Cells were rinsed with ice-cold medium 199 containing 5% BSA (binding medium), and the medium was replaced with ice-cold binding medium containing 0.5 nmol/L ¹²⁵I-labeled human recombinant TNF- (Amersham). After 1-hour incubation at 4°C, cells were washed 3 times with ice-cold binding medium and lysed with 0.5 mol/L NaOH, and radioactivity was determined by scintillation counting. Specific binding was calculated by subtracting the counts in the presence of 1000-fold excess unlabeled TNF-.

Electrophoretic Mobility Shift Assay
The double-strand oligonucleotides containing the NF-B consensus sequences (Gibco) were end-labeled with [³²P]dATP (DuPont-NEN) with thyroxine polynucleotide kinase. Nuclear extract (10 µg protein) prepared as previously described¹⁴ was incubated with 1x10⁵ cpm ³²P-labeled oligonucleotide for 20 minutes at room temperature in a binding buffer (Gibco). Electrophoresis was carried out with 5% native polyacrylamide gels. Gels were vacuum-dried and exposed to x-ray film overnight. In antibody supershift assays, nuclear extracts were preincubated with the antisera to p65, p50, p52, or c-Rel (Santa Cruz Biotechnology) for 30 minutes before the addition of the labeled probe. Competition studies were performed by addition of 100-fold excess unlabeled oligonucleotide to the binding reaction.

Immunoblot Analysis
Whole-cell lysates were resolved on 12.5% SDS-PAGE gels, followed by electrophoretic transfer to nitrocellulose membranes (Amersham). The membranes were exposed to primary antibodies, then exposed to secondary antibodies conjugated to HRP. The antibody was detected with a Phototope-HRP Western Detection Kit (New England Biolabs). Primary antibodies were anti–phospho-specific IB- (Ser32) rabbit polyclonal antibody, anti–IB- rabbit polyclonal antibody, anti–phospho-specific Jun N-terminal kinase (JNK) (Thr183/Tyr185) rabbit polyclonal antibody, anti–phospho-specific p38 kinase (Thr180/Tyr182) rabbit polyclonal antibody, anti–phospho-specific Akt kinase (Ser473) rabbit polyclonal antibody (all New England Biolabs), and anti-GAPDH mouse monoclonal antibody (Biogenesis).

cAMP Measurement
HAECs (2x10⁵ cells/well in 24-well plates) were stimulated with the indicated amount of adiponectin in medium 199 containing 0.5% FCS and 3% BSA for 18 hours. Dishes were placed on ice, and media were changed to ice-cold PBS to terminate the reaction. Intracellular cAMP was determined with an enzyme immunoassay kit (Amersham) according to the manufacturer’s instructions.

Slot Blot Analysis
Total cellular RNA was prepared from HAECs by RNA-Trizol extraction (Gibco). For slot blot analysis, 0.1 to 10 µg of total RNA was denatured and applied directly to nylon membranes (Amersham). The membranes were hybridized with human VCAM-1, E-selectin, or ICAM-1 probes labeled with [-³²P]dCTP by means of a random-primer labeling system (Amersham) as previously described.¹¹ Hybridization signals were quantified by scanning the films with a densitometer and comparing slopes (obtained by linear regression analysis) of signal areas versus total RNA loaded. We confirmed that each signal of VCAM-1, E-selectin, or ICAM-1 was detected as a single band by Northern blot analysis.¹¹

	Results

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Binding of Adiponectin to HAECs
To estimate the direct interaction between adiponectin and HAECs, we established a cell ELISA using biotinylated adiponectin. Biotinylated adiponectin interacted significantly with HAECs (Figure 1). The association of biotinylated adiponectin with HAECs occurred in a saturable manner at physiological concentrations (3 to 30 µg/mL) of adiponectin (Figure 1A) and was significantly suppressed by anti-adiponectin monoclonal antibody, ANOC 9104 (Figure 1B), suggesting that adiponectin specifically binds to HAECs.

View larger version (14K): [in this window] [in a new window]   Figure 1. Interaction of adiponectin with HAECs. A, Association of adiponectin with HAECs. HAECs were incubated with 0.5 to 30 µg/mL biotinylated adiponectin. Cell-surface association of biotinylated adiponectin was quantified by ELISA. Data are shown as mean±SD. Experiment was repeated 3 times, and data from 1 representative experiment are shown. B, Effect of anti-adiponectin monoclonal antibody on association of adiponectin with HAECs. HAECs were incubated with 10 µg/mL biotinylated adiponectin along with indicated amounts of anti-adiponectin mouse monoclonal antibody, ANOC 9104 (columns 3 and 4), or 30 µg/mL of nonimmune mouse IgG (column 2). Biotinylated nonimmune rabbit IgG (10 µg/mL) was used as a negative control (column 1). Columns and vertical bars denote mean and SD of 3 experiments. Representative results from 3 experiments are shown.

Adiponectin Does Not Affect TNF- Binding to HAECs
We recently demonstrated that adiponectin inhibited TNF-–induced adhesion molecule expression in HAECs.¹¹ To determine whether this inhibitory action of adiponectin was due to the inhibition of TNF- binding to its receptor on HAECs, we performed a TNF- binding assay. No significant difference was observed on ¹²⁵I-labeled TNF- binding between physiological concentrations of adiponectin-treated and nontreated HAECs (Figure 2). In addition, adiponectin treatment did not affect the cell-surface expression of TNF receptors determined by flow cytometry (data not shown). These results suggest that adiponectin suppressed the TNF-–induced signaling pathway at the postreceptor level.

View larger version (13K): [in this window] [in a new window]   Figure 2. Effect of adiponectin on TNF- binding to HAECs. HAECs were treated with indicated amount of adiponectin for 18 hours and then incubated with 125I-labeled TNF- for 1 hour at 4°C. Specific binding was calculated by subtracting counts in presence of excess amounts of unlabeled TNF- from total counts in absence of unlabeled TNF-. Basal counts were 824±48 cpm. Columns and vertical bars denote mean and SD of 3 experiments. Representative results from 3 experiments are shown.

Adiponectin Specifically Inhibits the IB-–NF-B Pathway Stimulated by TNF-
NF-B plays an important role in the transcriptional regulation of endothelial adhesion molecules stimulated by TNF-.¹³ We next examined the effect of adiponectin on TNF-–induced NF-B activation in HAECs by electrophoretic mobility shift assays using radiolabeled NF-B consensus oligonucleotides. Adiponectin treatment decreased the amount of DNA-binding complex induced by TNF- stimulation (Figure 3A, lanes 1 to 4), indicating that adiponectin suppressed TNF-–induced NF-B activation. In addition, antibody supershift experiments using antisera to Rel family members (Figure 3A, lanes 5 to 8) indicated that the TNF-–inducible NF-B complex was composed of p65 and p50 in HAECs. The specificity of NF-B DNA-binding complex was further confirmed by competition analyses using 100-fold excess cold unlabeled NF-B oligonucleotide (Figure 3A, lanes 9 and 10).

View larger version (19K): [in this window] [in a new window]   Figure 3. Effects of adiponectin on TNF- signaling in HAECs. A, Inhibitory effect of adiponectin on NF-B DNA-binding activity. HAECs were incubated with 50 µg/mL of adiponectin (lanes 2 and 4) or without it (lanes 1 and 3) and subsequently stimulated (60 minutes) by human recombinant TNF- (10 U/mL) (lanes 3 and 4) or vehicle (lanes 1 and 2). Subunit composition of DNA-binding complexes was determined by supershift experiments with antisera to p65 (lane 5), p50 (lane 6), p52 (lane 7), or c-Rel (lane 8). Competition experiments were performed by incubation with (lane 10) or without (lane 9) 100-fold excess unlabeled oligonucleotide (Ex.). Nuclear extracts were incubated with a 32P-labeled oligonucleotide probe containing NF-B consensus sequences. B, Time course of phosphorylated form of IB- in TNF-–stimulated HAECs without adiponectin (top) or with adiponectin (bottom). After 18-hour pretreatment with or without adiponectin (50 µg/mL), proteasomal inhibitor MG132 was added to complete media to a final concentration of 20 µmol/L for 1 hour, followed by TNF- (10 U/mL) stimulation for times indicated. Whole-cell lysates were fractionated by SDS-PAGE followed by immunoblotting with anti–phospho-specific IB- antibody. GAPDH was used as internal standard. C, Effect of ANOC 9104 on inhibition of IB- phosphorylation by adiponectin. After 18-hour treatment with adiponectin (50 µg/mL) in presence or absence of ANOC 9104 or nonimmune IgG (50 µg/mL), HAECs were incubated for 1 hour with MG132 (20 µmol/L) and stimulated for 20 minutes by TNF- (10 U/mL). Whole-cell lysates were immunoblotted with anti–phospho-specific IB- antibody. D, Degradation of IB- induced by TNF- without adiponectin (lanes 1, 2, and 3) or with adiponectin (lanes 4, 5, and 6). HAECs were preincubated for 18 hours with or without adiponectin (50 µg/mL), then treated with TNF- (10 U/mL) for times indicated. Whole-cell lysates were immunoblotted with anti–IB- antibody. E, Phosphorylated form of JNK (top), p38 kinase (middle), or Akt kinase (bottom) induced by TNF- (10 U/mL) without adiponectin (lanes 1, 2, and 3) or with 50 µg/mL of adiponectin (lanes 4 and 5). HAECs were treated by same procedure as in D. Whole-cell lysates were immunoblotted with anti–phospho-specific JNK antibody, anti–phospho-specific p38 kinase antibody, or anti–phospho-specific Akt kinase antibody. Data from 1 representative experiment of 3 are shown.

The activation of NF-B stimulated by TNF- is controlled by the rapid phosphorylation and degradation of the cytoplasmic inhibitor IB-.^{15 16 17} To determine whether adiponectin affects the phosphorylation of IB-, we examined the phosphorylation of IB- in HAECs using phosphospecific IB- antibody. The proteasome inhibitor MG132 was added 1 hour before TNF- stimulation to stabilize the phosphorylated form of IB-.¹⁶ Without adiponectin pretreatment, TNF-–induced phosphorylation of IB- peaked at 20 minutes after TNF- stimulation (Figure 3B). Adiponectin pretreatment significantly suppressed TNF-–stimulated IB- phosphorylation (Figure 3B). Furthermore, the suppressive effect of adiponectin on TNF-–induced IB- phosphorylation was blocked by cotreatment with adiponectin and anti-adiponectin monoclonal antibody, ANOC 9104 (Figure 3C), suggesting that this suppressive effect of adiponectin might be generated by specific interaction between adiponectin and HAECs. Without MG132 pretreatment, the total IB- protein amount was markedly decreased at 30 minutes after TNF- stimulation and returned to basal levels at 60 minutes (Figure 3D, lanes 1 to 3). Adiponectin pretreatment significantly blocked TNF-–mediated degradation of IB- protein at 30 minutes in the absence of MG132 (Figure 3D, lane 5). TNF- has been reported to activate several signaling pathways, including the JNK, p38, and Akt kinase pathways.^{18 19 20} In contrast to IB-, adiponectin pretreatment had no effect on TNF-–mediated phosphorylation of these kinases (Figure 3E).

Inhibitory Mechanism of TNF-–Induced IB- Phosphorylation by Adiponectin
Previous reports showed that elevation of cAMP reduced NF-B activity through stabilization of IB-.^{21 22} Adiponectin treatment dose-dependently increased cAMP levels in HAECs (Figure 4A). Pretreatment of HAECs with low doses of exogenous cAMP (dibutyryl cAMP) (0.5 to 10 µmol/L) for 18 hours dose-dependently reduced TNF-–induced IB- phosphorylation (Figure 4B), suggesting that the inhibitory effect of adiponectin on the NF-B pathway could be mimicked by other ways to increase cAMP. To examine whether adiponectin modulates TNF-–induced IB- phosphorylation through a cAMP-dependent pathway, we next investigated the effect of ddAdo, a potent inhibitor of adenylate cyclase that is responsible for the generation of cAMP, on the inhibition of TNF-–induced IB- phosphorylation by adiponectin. The suppressive effect of adiponectin on TNF-–induced IB- phosphorylation was blocked by pretreatment with ddAdo (200 µmol/L) (Figure 4C). Because cAMP is known to activate PKA, we examined the effect of the specific PKA inhibitor Rp-cAMP on IB- phosphorylation. Pretreatment with Rp-cAMP (10 µmol/L) also blocked the inhibitory effect of adiponectin on TNF-–induced IB- phosphorylation (Figure 4C). Pretreatment with ddAdo or Rp-cAMP did not interfere with TNF-–induced IB- phosphorylation in the absence of adiponectin (data not shown). In addition, pretreatment with ddAdo or Rp-cAMP reversed the suppressive effect of adiponectin on TNF-–induced VCAM-1, E-selectin, or ICAM-1 mRNA levels measured by slot blot analysis (Figure 4D). These results indicated that this inhibitory effect of adiponectin is mediated through activation of cAMP-PKA pathway.

View larger version (29K): [in this window] [in a new window]   Figure 4. Involvement of cAMP pathway in inhibitory effect of adiponectin on TNF-–induced IB- phosphorylation in HAECs. A, Effect of adiponectin on cAMP accumulation in HAECs. HAECs were stimulated with indicated amount of adiponectin for 18 hours, and cytosolic cAMP was measured. Columns and vertical bars denote mean and SD of 3 experiments. B, Effect of dibutyryl cAMP (db-cAMP) on TNF-–induced IB- phosphorylation in HAECs. After 18-hour pretreatment with indicated concentration of db-cAMP, HAECs were incubated for 1 hour with MG132 (20 µmol/L), followed by TNF- (10 U/mL) stimulation for 20 minutes. Whole-cell lysates were immunoblotted with anti–phospho-specific IB- antibody. C, Reverse effect of adenylate cyclase or PKA inhibitor on adiponectin-induced suppression of TNF-–stimulated IB- phosphorylation. After pretreatment with ddAdo (200 µmol/L), Rp-cAMP (10 µmol/L), or vehicle for 1 hour, HAECs were treated as described in Figure 3B. D, Effect of adenylate cyclase or PKA inhibitor on VCAM-1, E-selectin, or ICAM-1 mRNA levels. After pretreatment with ddAdo (200 µmol/L), Rp-cAMP (10 µmol/L), or vehicle for 1 hour, HAECs were treated for 18 hours with 50 µg/mL of adiponectin, then incubated for 4 hours with TNF- (10 U/mL). mRNA levels of VCAM-1, E-selectin, or ICAM-1 were determined by slot blot analysis. Columns and vertical bars denote mean and SD of 3 experiments. Representative results from 3 experiments are shown.

	Discussion

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In the present study, we demonstrated that adiponectin specifically suppressed TNF-–induced IB-–NF-B activation through a cAMP-dependent pathway in HAECs. This finding indicated that adiponectin acts as an endogenous modulator for endothelial inflammatory response. NF-B is known to play a central role in the regulation of inflammatory reactions in various types of cells.^{23 24} NF-B activation by various inflammatory cytokines, including TNF-, results in the induction of endothelial adhesion molecules, such as VCAM-1, E-selectin, and ICAM-1, that participate in the recruitment of leukocytes to inflammatory lesions.^{12 13} This abnormal leukocyte adhesion to the vascular wall is considered crucial for the development of atherosclerosis.¹² Activated NF-B has been reported to be present in human atherosclerotic lesions.²⁵ We have found that adiponectin suppressed TNF-–induced adhesion molecule expression on HAECs. If adiponectin could modulate the excess inflammatory response, this natural substance in blood circulation might prevent atherogenesis as an anti-inflammatory factor.

It is a matter of great importance to clarify a molecular link between fat accumulation and vascular disease, because obesity is associated with increased cardiovascular mortality and morbidity.^{6 7 8} Adiponectin is an adipocyte-derived plasma protein that is abundantly present in the human blood stream.¹⁰ Plasma adiponectin levels in obese subjects were significantly lower than those in nonobese subjects,¹⁰ although adiponectin is expressed only in adipose tissue. Recently, we investigated the possibility that plasma adiponectin levels were significantly low in patients with CAD compared with those in age- and body mass index–adjusted control subjects,¹¹ suggesting that the decreased plasma adiponectin level may relate to the development of CAD through endothelial dysfunction. Overall, the measurement of plasma adiponectin levels may be beneficial in assessment of CAD risk, although a prospective study is necessary to clarify the relationship between CAD and reduced levels of plasma adiponectin.

NF-B inducing kinase (NIK) phosphorylates the IB kinase (IKK) complex, leading to IB phosphorylation and subsequent NF-B activation.²⁶ TNF-receptor–associated factor 2, an upstream docking protein linking NIK in the TNF- signaling pathway, has been shown to be the bifurcation point of TNF-–induced activation of NIK–NF-B and activation of JNK or p38 pathways.²⁷ NIK has not been involved in the activation of JNK and p38 kinases.²⁷ In this study, adiponectin associated with HAECs in a saturable manner and dose-dependently accumulated cAMP in HAECs. It has been reported that activation of cAMP-PKA signaling attenuated NF-B activity through stabilization of IB-, although its precise mechanism has not been clarified.^{21 22} Adiponectin specifically suppressed TNF-–induced activation of the IB-–NF-B pathway without affecting the phosphorylation of JNK, p38, or Akt kinase, indicating that adiponectin reduced the TNF-–induced NF-B signaling pathway at the level between NIK and IB-. The suppressive effect of adiponectin on IB- phosphorylation was completely blocked by the antagonists of the adenylate cyclase pathway, although these agents did not fully reverse the mRNA levels of monocyte adhesion molecules. These results suggest that adiponectin may have a cAMP-PKA–independent effect on TNF-–induced adhesion molecule expression. Recently, Akt kinase–mediated IKK phosphorylation was reported to activate the IB–NF-B pathway.²⁰ Because adiponectin did not affect TNF-–stimulated Akt kinase, TNF-–induced mRNA levels of monocyte adhesion molecules might be partially decreased by adiponectin treatment. In summary, adiponectin affects the adenylate cyclase–coupled molecule and attenuates TNF-–mediated inflammatory response through cAMP-PKA pathway activation, although further investigation is needed to clarify the mechanism by which adiponectin activates the cAMP-PKA pathway.

Adiponectin, an adipocyte-specific plasma protein, acts as an endogenous biologically relevant modulator of endothelial cell responses to proinflammatory stimuli through cross talk between cAMP-PKA and NF-B signaling pathways. Our observations provide a fundamental mechanism for the link between obesity and vascular disease.

	Acknowledgments

 
This work was supported by grants from the Japanese Ministry of Education and the Japan Society for Promotion of Science Research for the Future Program.

Received March 15, 2000; revision received April 11, 2000; accepted April 13, 2000.

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				C. Herder, A. Zierer, W. Koenig, M. Roden, C. Meisinger, and B. Thorand Transforming Growth Factor-{beta}1 and Incident Type 2 Diabetes: Results from the MONICA/KORA case-cohort study, 1984-2002 Diabetes Care, October 1, 2009; 32(10): 1921 - 1923. [Abstract] [Full Text] [PDF]

				M. K. Duda, K. M. O'Shea, and W. C. Stanley {omega}-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential Cardiovasc Res, October 1, 2009; 84(1): 33 - 41. [Abstract] [Full Text] [PDF]

				E. J. Folco, V. Z. Rocha, M. Lopez-Ilasaca, and P. Libby Adiponectin Inhibits Pro-inflammatory Signaling in Human Macrophages Independent of Interleukin-10 J. Biol. Chem., September 18, 2009; 284(38): 25569 - 25575. [Abstract] [Full Text] [PDF]

				R. B. Goldberg Cytokine and Cytokine-Like Inflammation Markers, Endothelial Dysfunction, and Imbalanced Coagulation in Development of Diabetes and Its Complications J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3171 - 3182. [Abstract] [Full Text] [PDF]

				R. Summer, C. A. Fiack, Y. Ikeda, K. Sato, D. Dwyer, N. Ouchi, A. Fine, H. W. Farber, and K. Walsh Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease Am J Physiol Lung Cell Mol Physiol, September 1, 2009; 297(3): L432 - L438. [Abstract] [Full Text] [PDF]

				M. A. Aminzadeh, M. V. Pahl, C. H. Barton, N. S. Doctor, and N. D. Vaziri Human uraemic plasma stimulates release of leptin and uptake of tumour necrosis factor-{alpha} in visceral adipocytes Nephrol. Dial. Transplant., August 7, 2009; (2009) gfp405v1. [Abstract] [Full Text] [PDF]

				J. F. Ndisang and A. Jadhav Up-Regulating the Hemeoxygenase System Enhances Insulin Sensitivity and Improves Glucose Metabolism in Insulin-Resistant Diabetes in Goto-Kakizaki Rats Endocrinology, June 1, 2009; 150(6): 2627 - 2636. [Abstract] [Full Text] [PDF]

				J. F. Ndisang, N. lane, and A. Jadhav The Heme Oxygenase System Abates Hyperglycemia in Zucker Diabetic Fatty Rats by Potentiating Insulin-Sensitizing Pathways Endocrinology, May 1, 2009; 150(5): 2098 - 2108. [Abstract] [Full Text] [PDF]

				J. F. Ndisang, N. Lane, and A. Jadhav Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes Am J Physiol Endocrinol Metab, May 1, 2009; 296(5): E1029 - E1041. [Abstract] [Full Text] [PDF]

				A. A. Mahabadi, J. M. Massaro, G. A. Rosito, D. Levy, J. M. Murabito, P. A. Wolf, C. J. O'Donnell, C. S. Fox, and U. Hoffmann Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study Eur. Heart J., April 1, 2009; 30(7): 850 - 856. [Abstract] [Full Text] [PDF]

				J. F. Ndisang and A. Jadhav Heme oxygenase system enhances insulin sensitivity and glucose metabolism in streptozotocin-induced diabetes Am J Physiol Endocrinol Metab, April 1, 2009; 296(4): E829 - E841. [Abstract] [Full Text] [PDF]

				M. K. Duda, K. M. O'Shea, A. Tintinu, W. Xu, R. J. Khairallah, B. R. Barrows, D. J. Chess, A. M. Azimzadeh, W. S. Harris, V. G. Sharov, et al. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction Cardiovasc Res, February 1, 2009; 81(2): 319 - 327. [Abstract] [Full Text] [PDF]

				F. Moukdar, J. Robidoux, O. Lyght, J. Pi, K. W. Daniel, and S. Collins Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice J. Lipid Res., January 1, 2009; 50(1): 59 - 70. [Abstract] [Full Text] [PDF]

				P. Zhang, Y. Wang, Y. Fan, Z. Tang, and N. Wang Overexpression of Adiponectin Receptors Potentiates the Antiinflammatory Action of Subeffective Dose of Globular Adiponectin in Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 67 - 74. [Abstract] [Full Text] [PDF]

				M Kohler, L Ayers, J C T Pepperell, K L Packwood, B Ferry, N Crosthwaite, S Craig, M M Siccoli, R J O Davies, and J R Stradling Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial Thorax, January 1, 2009; 64(1): 67 - 73. [Abstract] [Full Text] [PDF]

				S. S. Deepa and L. Q. Dong APPL1: role in adiponectin signaling and beyond Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E22 - E36. [Abstract] [Full Text] [PDF]

				M. J. Puglisi and M. L. Fernandez Modulation of C-Reactive Protein, Tumor Necrosis Factor-{alpha}, and Adiponectin by Diet, Exercise, and Weight Loss J. Nutr., December 1, 2008; 138(12): 2293 - 2296. [Abstract] [Full Text] [PDF]

				J. Axelsson The emerging biology of adipose tissue in chronic kidney disease: from fat to facts Nephrol. Dial. Transplant., October 1, 2008; 23(10): 3041 - 3046. [Full Text] [PDF]

				A. Bakhai Adipokines--targeting a root cause of cardiometabolic risk QJM, October 1, 2008; 101(10): 767 - 776. [Abstract] [Full Text] [PDF]

				B. Chandrasekar, W. H. Boylston, K. Venkatachalam, N. J. G. Webster, S. D. Prabhu, and A. J. Valente Adiponectin Blocks Interleukin-18-mediated Endothelial Cell Death via APPL1-dependent AMP-activated Protein Kinase (AMPK) Activation and IKK/NF-{kappa}B/PTEN Suppression J. Biol. Chem., September 5, 2008; 283(36): 24889 - 24898. [Abstract] [Full Text] [PDF]

				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]

				M. Pini, M. E. Gove, J. A. Sennello, J. W. P. M. van Baal, L. Chan, and G. Fantuzzi Role and Regulation of Adipokines during Zymosan-Induced Peritoneal Inflammation in Mice Endocrinology, August 1, 2008; 149(8): 4080 - 4085. [Abstract] [Full Text] [PDF]

				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]

				N. Ouchi and K. Walsh A Novel Role for Adiponectin in the Regulation of Inflammation Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1219 - 1221. [Full Text] [PDF]

				J. Malyszko, J.S. Malyszko, P. Kozminski, K. Pawlak, and M. Mysliwiec Adipokines, Linking Adipocytes and Vascular Function in Hemodialyzed Patients, May Also Be Possibly Related to CD146, a Novel Adhesion Molecule Clinical and Applied Thrombosis/Hemostasis, July 1, 2008; 14(3): 338 - 345. [Abstract] [PDF]

				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]

				N Beraza, Y Malato, S Vander Borght, C Liedtke, H E Wasmuth, M Dreano, R de Vos, T Roskams, and C Trautwein Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis Gut, May 1, 2008; 57(5): 655 - 663. [Abstract] [Full Text] [PDF]

				P.-h. Park, H. Huang, M. R. McMullen, K. Bryan, and L. E. Nagy Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in raw 264.7 macrophages J. Leukoc. Biol., May 1, 2008; 83(5): 1258 - 1266. [Abstract] [Full Text] [PDF]

				S.-Q. Xu, K. Mahadev, X. Wu, L. Fuchsel, S. Donnelly, R. G. Scalia, and B. J. Goldstein Adiponectin Protects Against Angiotensin II or Tumor Necrosis Factor {alpha}-Induced Endothelial Cell Monolayer Hyperpermeability: Role of cAMP/PKA Signaling Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 899 - 905. [Abstract] [Full Text] [PDF]

				K. Mahadev, X. Wu, S. Donnelly, R. Ouedraogo, A. D. Eckhart, and B. J. Goldstein Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells Cardiovasc Res, May 1, 2008; 78(2): 376 - 384. [Abstract] [Full Text] [PDF]

				B.-K. Son, M. Akishita, K. Iijima, K. Kozaki, K. Maemura, M. Eto, and Y. Ouchi Adiponectin Antagonizes Stimulatory Effect of Tumor Necrosis Factor-{alpha} on Vascular Smooth Muscle Cell Calcification: Regulation of Growth Arrest-Specific Gene 6-Mediated Survival Pathway by Adenosine 5'-Monophosphate-Activated Protein Kinase Endocrinology, April 1, 2008; 149(4): 1646 - 1653. [Abstract] [Full Text] [PDF]

				R. Schnabel, C. M. Messow, E. Lubos, C. Espinola-Klein, H. J. Rupprecht, C. Bickel, C. Sinning, S. Tzikas, T. Keller, S. Genth-Zotz, et al. Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study Eur. Heart J., March 1, 2008; 29(5): 649 - 657. [Abstract] [Full Text] [PDF]

				R. W. Nesto and K. Mackie Endocannabinoid system and its implications for obesity and cardiometabolic risk Eur. Heart J. Suppl., March 1, 2008; 10(suppl_B): B34 - B41. [Abstract] [Full Text] [PDF]

				K. O. Badellino, M. L. Wolfe, M. P. Reilly, and D. J. Rader Endothelial Lipase Is Increased In Vivo by Inflammation in Humans Circulation, February 5, 2008; 117(5): 678 - 685. [Abstract] [Full Text] [PDF]

				E. L Madsen, A. Rissanen, J. M Bruun, K. Skogstrand, S. Tonstad, D. M Hougaard, and B. Richelsen Weight loss larger than 10% is needed for general improvement of levels of circulating adiponectin and markers of inflammation in obese subjects: a 3-year weight loss study Eur. J. Endocrinol., February 1, 2008; 158(2): 179 - 187. [Abstract] [Full Text] [PDF]

				S. Steffens and F. Mach Adiponectin and Adaptive Immunity: Linking the Bridge From Obesity to Atherogenesis Circ. Res., February 1, 2008; 102(2): 140 - 142. [Full Text] [PDF]

				Y. Okamoto, E. J. Folco, M. Minami, A.K. Wara, M. W. Feinberg, G. K. Sukhova, R. A. Colvin, S. Kihara, T. Funahashi, A. D. Luster, et al. Adiponectin Inhibits the Production of CXC Receptor 3 Chemokine Ligands in Macrophages and Reduces T-Lymphocyte Recruitment in Atherogenesis Circ. Res., February 1, 2008; 102(2): 218 - 225. [Abstract] [Full Text] [PDF]

				D Barb, A Neuwirth, C S Mantzoros, and S P Balk Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway Endocr. Relat. Cancer, December 1, 2007; 14(4): 995 - 1005. [Abstract] [Full Text] [PDF]

				X. Wu, K. Mahadev, L. Fuchsel, R. Ouedraogo, S.-q. Xu, and B. J. Goldstein Adiponectin suppresses I{kappa}B kinase activation induced by tumor necrosis factor-{alpha} or high glucose in endothelial cells: role of cAMP and AMP kinase signaling Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1836 - E1844. [Abstract] [Full Text] [PDF]

				F. Haugen and C. A. Drevon Activation of Nuclear Factor-{kappa}B by High Molecular Weight and Globular Adiponectin Endocrinology, November 1, 2007; 148(11): 5478 - 5486. [Abstract] [Full Text] [PDF]

				B. Gustafson, A. Hammarstedt, C. X. Andersson, and U. Smith Inflamed Adipose Tissue: A Culprit Underlying the Metabolic Syndrome and Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2276 - 2283. [Abstract] [Full Text] [PDF]

				L. Cong, J. Gasser, J. Zhao, B. Yang, F. Li, and A. Z Zhao Human adiponectin inhibits cell growth and induces apoptosis in human endometrial carcinoma cells, HEC-1-A and RL95 2 Endocr. Relat. Cancer, September 1, 2007; 14(3): 713 - 720. [Abstract] [Full Text] [PDF]

				D. Barb, C. J Williams, A. K Neuwirth, and C. S Mantzoros Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence Am. J. Clinical Nutrition, September 1, 2007; 86(3): 858S - 866S. [Abstract] [Full Text] [PDF]

				J. Dominguez, P. Wu, C. S. Packer, C. Temm, and K. J. Kelly Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy Am J Physiol Renal Physiol, September 1, 2007; 293(3): F670 - F679. [Abstract] [Full Text] [PDF]

				N. Echahidi, P. Pibarot, J.-P. Despres, J.-M. Daigle, D. Mohty, P. Voisine, R. Baillot, and P. Mathieu Metabolic Syndrome Increases Operative Mortality in Patients Undergoing Coronary Artery Bypass Grafting Surgery J. Am. Coll. Cardiol., August 28, 2007; 50(9): 843 - 851. [Abstract] [Full Text] [PDF]

				S. G. Wannamethee, P. H. Whincup, L. Lennon, and N. Sattar Circulating Adiponectin Levels and Mortality in Elderly Men With and Without Cardiovascular Disease and Heart Failure Arch Intern Med, July 23, 2007; 167(14): 1510 - 1517. [Abstract] [Full Text] [PDF]

				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]

				Y. Hattori and Y. Nakano Response to Comment on: Goldstein et al. (2007) Globular Adiponectin Activates Nuclear Factor-{kappa}B and Activating Protein-1 and Enhances Angiotensin II-Induced Proliferation in Cardiac Fibroblasts: Diabetes 56:804-808 Diabetes, July 1, 2007; 56(7): e9 - e10. [Full Text] [PDF]

				K. Tomoda, M. Yoshikawa, T. Itoh, S. Tamaki, A. Fukuoka, K. Komeda, and H. Kimura Elevated Circulating Plasma Adiponectin in Underweight Patients With COPD Chest, July 1, 2007; 132(1): 135 - 140. [Abstract] [Full Text] [PDF]

				W.-S. Chow, B. M.Y. Cheung, A. W.K. Tso, A. Xu, N. M.S. Wat, C. H.Y. Fong, L. H.Y. Ong, S. Tam, K. C.B. Tan, E. D. Janus, et al. Hypoadiponectinemia as a Predictor for the Development of Hypertension: A 5-Year Prospective Study Hypertension, June 1, 2007; 49(6): 1455 - 1461. [Abstract] [Full Text] [PDF]

				M. G. Flynn, B. K. McFarlin, and M. M. Markofski State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training American Journal of Lifestyle Medicine, May 1, 2007; 1(3): 220 - 235. [Abstract] [PDF]

				N. Pischon, N. Heng, J.-P. Bernimoulin, B.-M. Kleber, S.N. Willich, and T. Pischon Obesity, Inflammation, and Periodontal Disease Journal of Dental Research, May 1, 2007; 86(5): 400 - 409. [Abstract] [Full Text] [PDF]

				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]

				K. K.Y. Cheng, K. S.L. Lam, Y. Wang, Y. Huang, D. Carling, D. Wu, C. Wong, and A. Xu Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells Diabetes, May 1, 2007; 56(5): 1387 - 1394. [Abstract] [Full Text] [PDF]

				J. W. Bullen Jr., S. Bluher, T. Kelesidis, and C. S. Mantzoros Regulation of adiponectin and its receptors in response to development of diet-induced obesity in mice Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1079 - E1086. [Abstract] [Full Text] [PDF]

				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]

				M. E. Trujillo and P. E. Scherer Adipose Tissue-Derived Factors: Impact on Health and Disease Endocr. Rev., December 1, 2006; 27(7): 762 - 778. [Abstract] [Full Text] [PDF]

				H. Takano, Y. Kodama, Y. Kitta, T. Nakamura, J.-e. Obata, A. Mende, K.-i. Kawabata, Y. Saitoh, D. Fujioka, T. Kobayashi, et al. Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2641 - H2646. [Abstract] [Full Text] [PDF]

				S. Ledoux, D. B. Campos, F. L. Lopes, M. Dobias-Goff, M.-F. Palin, and B. D. Murphy Adiponectin Induces Periovulatory Changes in Ovarian Follicular Cells Endocrinology, November 1, 2006; 147(11): 5178 - 5186. [Abstract] [Full Text] [PDF]

				K. Kantartzis, K. Rittig, B. Balletshofer, J. Machann, F. Schick, K. Porubska, A. Fritsche, H.-U. Haring, and N. Stefan The Relationships of Plasma Adiponectin with a Favorable Lipid Profile, Decreased Inflammation, and Less Ectopic Fat Accumulation Depend on Adiposity Clin. Chem., October 1, 2006; 52(10): 1934 - 1942. [Abstract] [Full Text] [PDF]

				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]

				N. Sattar, G. Wannamethee, N. Sarwar, J. Tchernova, L. Cherry, A. M. Wallace, J. Danesh, and P. H. Whincup Adiponectin and Coronary Heart Disease: A Prospective Study and Meta-Analysis Circulation, August 15, 2006; 114(7): 623 - 629. [Abstract] [Full Text] [PDF]

				A. Schaffler, U. Muller-Ladner, J. Scholmerich, and C. Buchler Role of Adipose Tissue as an Inflammatory Organ in Human Diseases Endocr. Rev., August 1, 2006; 27(5): 449 - 467. [Abstract] [Full Text] [PDF]

				Y. Nakano, S. Tajima, A. Yoshimi, H. Akiyama, M. Tsushima, T. Tanioka, T. Negoro, M. Tomita, and T. Tobe A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin J. Lipid Res., July 1, 2006; 47(7): 1572 - 1582. [Abstract] [Full Text] [PDF]

				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]

				P. Trayhurn, C. Bing, and I. S. Wood Adipose Tissue and Adipokines--Energy Regulation from the Human Perspective J. Nutr., July 1, 2006; 136(7): 1935S - 1939S. [Abstract] [Full Text] [PDF]

				M. Nishimura, T. Hashimoto, H. Kobayashi, S. Yamazaki, K. Okino, H. Fujita, N. Inoue, H. Takahashi, and T. Ono Association of the circulating adiponectin concentration with coronary in-stent restenosis in haemodialysis patients Nephrol. Dial. Transplant., June 1, 2006; 21(6): 1640 - 1647. [Abstract] [Full Text] [PDF]

				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]

				K. Ohashi, S. Kihara, N. Ouchi, M. Kumada, K. Fujita, A. Hiuge, T. Hibuse, M. Ryo, H. Nishizawa, N. Maeda, et al. Adiponectin Replenishment Ameliorates Obesity-Related Hypertension Hypertension, June 1, 2006; 47(6): 1108 - 1116. [Abstract] [Full Text] [PDF]

				K.-y. Kim, J. K. Kim, S. H. Han, J.-S. Lim, K. I. Kim, D. H. Cho, M.-S. Lee, J.-H. Lee, D.-Y. Yoon, S. R. Yoon, et al. Adiponectin Is a Negative Regulator of NK Cell Cytotoxicity J. Immunol., May 15, 2006; 176(10): 5958 - 5964. [Abstract] [Full Text] [PDF]

				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]

				J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms Circulation, April 18, 2006; 113(15): 1888 - 1904. [Abstract] [Full Text] [PDF]

				H. Ekmekci and O. B. Ekmekci The Role of Adiponectin in Atherosclerosis and Thrombosis Clinical and Applied Thrombosis/Hemostasis, April 1, 2006; 12(2): 163 - 168. [Abstract] [PDF]

				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]

				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]

				M. Mohlig, M. Freudenberg, T. Bobbert, M. Ristow, H. Rochlitz, M. O. Weickert, A. F. H. Pfeiffer, and J. Spranger Acetylsalicylic Acid Improves Lipid-Induced Insulin Resistance in Healthy Men J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 964 - 967. [Abstract] [Full Text] [PDF]

				F. Abbasi, S.-A. Chang, J. W. Chu, T. P. Ciaraldi, C. Lamendola, T. McLaughlin, G. M. Reaven, and P. D. Reaven Improvements in insulin resistance with weight loss, in contrast to rosiglitazone, are not associated with changes in plasma adiponectin or adiponectin multimeric complexes Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R139 - R144. [Abstract] [Full Text] [PDF]

				F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]

				R. M. Touyz Endothelial Cell IL-8, a New Target for Adiponectin: Implications in Vascular Protection Circ. Res., December 9, 2005; 97(12): 1216 - 1219. [Full Text] [PDF]

				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]

				K. K. Koh, S. H. Han, and M. J. Quon Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1978 - 1985. [Abstract] [Full Text] [PDF]

				B. Iglseder, V. Mackevics, A. Stadlmayer, G. Tasch, G. Ladurner, and B. Paulweber Plasma Adiponectin Levels and Sonographic Phenotypes of Subclinical Carotid Artery Atherosclerosis: Data From the SAPHIR Study Stroke, December 1, 2005; 36(12): 2577 - 2582. [Abstract] [Full Text] [PDF]

				N. Stefan, A. Fritsche, and H.-U. Haring Insulin Resistance and Congestive Heart Failure JAMA, November 23, 2005; 294(20): 2578 - 2578. [Full Text] [PDF]

				S. Maddineni, S. Metzger, O. Ocon, G. Hendricks III, and R. Ramachandran Adiponectin Gene Is Expressed in Multiple Tissues in the Chicken: Food Deprivation Influences Adiponectin Messenger Ribonucleic Acid Expression Endocrinology, October 1, 2005; 146(10): 4250 - 4256. [Abstract] [Full Text] [PDF]

				J. G. Schneider, M. von Eynatten, S. Schiekofer, P. P. Nawroth, and K. A. Dugi Low Plasma Adiponectin Levels Are Associated With Increased Hepatic Lipase Activity In Vivo Diabetes Care, September 1, 2005; 28(9): 2181 - 2186. [Abstract] [Full Text] [PDF]

				C. S. Mantzoros, T. Li, J. E. Manson, J. B. Meigs, and F. B. Hu Circulating Adiponectin Levels Are Associated with Better Glycemic Control, More Favorable Lipid Profile, and Reduced Inflammation in Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4542 - 4548. [Abstract] [Full Text] [PDF]

				M. Lappas, M. Permezel, and G. E. Rice Leptin and Adiponectin Stimulate the Release of Proinflammatory Cytokines and Prostaglandins from Human Placenta and Maternal Adipose Tissue via Nuclear Factor-{kappa}B, Peroxisomal Proliferator-Activated Receptor-{gamma} and Extracellularly Regulated Kinase 1/2 Endocrinology, August 1, 2005; 146(8): 3334 - 3342. [Abstract] [Full Text] [PDF]

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