(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
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
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
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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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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]
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 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]
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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]
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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]
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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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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]
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 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]
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 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]
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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]
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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]
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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]
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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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Y. Fu, N. Luo, R. L. Klein, and W. T. Garvey Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation J. Lipid Res., July 1, 2005; 46(7): 1369 - 1379. [Abstract] [Full Text] [PDF]
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D. Dietze-Schroeder, H. Sell, M. Uhlig, M. Koenen, and J. Eckel Autocrine Action of Adiponectin on Human Fat Cells Prevents the Release of Insulin Resistance-Inducing Factors Diabetes, July 1, 2005; 54(7): 2003 - 2011. [Abstract] [Full Text] [PDF]
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A Schaffler and H Herfarth Creeping fat in Crohn's disease: travelling in a creeper lane of research? Gut, June 1, 2005; 54(6): 742 - 744. [Full Text] [PDF]
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K Yamamoto, T Kiyohara, Y Murayama, S Kihara, Y Okamoto, T Funahashi, T Ito, R Nezu, S Tsutsui, J-I Miyagawa, et al. Production of adiponectin, an anti-inflammatory protein, in mesenteric adipose tissue in Crohn's disease Gut, June 1, 2005; 54(6): 789 - 796. [Abstract] [Full Text] [PDF]
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 A. Reifel-Miller, K. Otto, E. Hawkins, R. Barr, W. R. Bensch, C. Bull, S. Dana, K. Klausing, J.-A. Martin, R. Rafaeloff-Phail, et al. A Peroxisome Proliferator-Activated Receptor {alpha}/{gamma} Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia Mol. Endocrinol., June 1, 2005; 19(6): 1593 - 1605. [Abstract] [Full Text] [PDF]
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 S. Otake, H. Takeda, Y. Suzuki, T. Fukui, S. Watanabe, K. Ishihama, T. Saito, H. Togashi, T. Nakamura, Y. Matsuzawa, et al. Association of Visceral Fat Accumulation and Plasma Adiponectin with Colorectal Adenoma: Evidence for Participation of Insulin Resistance Clin. Cancer Res., May 15, 2005; 11(10): 3642 - 3646. [Abstract] [Full Text] [PDF]
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T. Kadowaki and T. Yamauchi Adiponectin and Adiponectin Receptors Endocr. Rev., May 1, 2005; 26(3): 439 - 451. [Abstract] [Full Text] [PDF]
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E. S. Kang, S. Y. Park, H. J. Kim, C. W. Ahn, M. Nam, B. S. Cha, S. K. Lim, K. R. Kim, and H. C. Lee The Influence of Adiponectin Gene Polymorphism on the Rosiglitazone Response in Patients With Type 2 Diabetes Diabetes Care, May 1, 2005; 28(5): 1139 - 1144. [Abstract] [Full Text] [PDF]
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J. A. Sennello, R. Fayad, A. M. Morris, R. H. Eckel, E. Asilmaz, J. Montez, J. M. Friedman, C. A. Dinarello, and G. Fantuzzi Regulation of T Cell-Mediated Hepatic Inflammation by Adiponectin and Leptin Endocrinology, May 1, 2005; 146(5): 2157 - 2164. [Abstract] [Full Text] [PDF]
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