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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:635.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effects of Peroxisome Proliferator-Activated Receptor Ligands, Bezafibrate and Fenofibrate, on Adiponectin Level

Aki Hiuge; Alexander Tenenbaum; Norikazu Maeda; Michal Benderly; Masahiro Kumada; Enrique Z. Fisman; David Tanne; Zipora Matas; Toshiyuki Hibuse; Koichi Fujita; Hitoshi Nishizawa; Yehuda Adler; Michael Motro; Shinji Kihara; Iichiro Shimomura; Solomon Behar; Tohru Funahashi

From Department of Metabolic Medicine (A.H., N.M., M.K., T.H., K.F., H.N., S.K., I.S., T.F.), Graduate School of Medicine, Osaka University, Osaka, Japan; Cardiac Rehabilitation Institute (A.T., E.Z.F., Y.A., M.M.), The Israel Society for the Prevention of Hearth Attacks (ISPHA) (M.B., D.T., S.B.), the Bezafibrate Infarction Prevention Study Coordinating Center, Neufeld Cardiac Research Institute, the Chaim Sheba Medical Center, Tel-Hashomer; Biochemistry Laboratory (Z.M.), Wolfson Medical Center, Holon, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Correspondence to Norikazu Maeda, MD, PhD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, B5, Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail nmaeda{at}imed2.med.osaka-u.ac.jp

Objective— Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPAR ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells.

Methods and Results— Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPAR-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPAR was knocked down by PPAR-RNAi.

Conclusions— Our results suggest that fibrates enhance adiponectin partly through adipose PPAR and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Subanalysis of BIP study showed that bezafibrate significantly increased serum adiponectin and higher baseline adiponectin levels were associated with reduced risk of new diabetes. A series of experiments by using PPAR-deficient mice and cells indicated that fibrates enhance adiponectin partly through adipose PPAR.

Key Words: adipocyte • adiponectin • fibrate • metabolic syndrome • peroxisome proliferator-activated receptor

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