Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.
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 PPARalpha 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.


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 PPARalpha-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 PPARalpha was knocked down by PPARalpha-RNAi.


CONCLUSIONS
Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.
Hiuge
Aki
A
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2, B5, Yamada-oka, Suita, Osaka 565-0871, Japan.
Tenenbaum
Alexander
A
Maeda
Norikazu
N
Benderly
Michal
M
Kumada
Masahiro
M
Fisman
Enrique Z
EZ
Tanne
David
D
Matas
Zipora
Z
Hibuse
Toshiyuki
T
Fujita
Koichi
K
Nishizawa
Hitoshi
H
Adler
Yehuda
Y
Motro
Michael
M
Kihara
Shinji
S
Shimomura
Iichiro
I
Behar
Solomon
S
Funahashi
Tohru
T
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001629:Bezafibrate / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D011336:Probability; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D018709:Statistics, Nonparametric; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D052242:Adiponectin; D000960:Hypolipidemic Agents; D008024:Ligands; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D011345:Fenofibrate; D001629:Bezafibrate