CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression.
BACKGROUND
An increased level of obesity-induced plasma plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular disease.


OBJECTIVE
The present study investigates whether the circadian clock component CLOCK is involved in obesity-induced PAI-1 elevation.


METHODS
We examined plasma PAI-1 and mRNA expression levels in tissues from leptin-deficient obese and diabetic ob/ob mice lacking functional CLOCK protein.


RESULTS
Our results demonstrated that plasma PAI-1 levels were augmented in a circadian manner in accordance with the mRNA expression levels in ob/ob mice. Surprisingly, a Clock mutation normalized the plasma PAI-1 concentrations in accordance with the mRNA levels in the heart, lung and liver of ob/ob mice, but significantly increased PAI-1 mRNA levels in adipose tissue by inducing adipocyte hypertrophy in ob/ob mice. The Clock mutation also normalized tissue PAI-1 antigen levels in the liver but not in the adipose tissue of ob/ob mice.


CONCLUSIONS
These observations suggest that CLOCK is involved in obesity-induced disordered fibrinolysis by regulating PAI-1 gene expression in a tissue-dependent manner. Furthermore, it appears that obesity-induced PAI-1 production in adipose tissue is not closely related to systemic PAI-1 increases in vivo.
Oishi
K
K
Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki, Japan.
Ohkura
N
N
Wakabayashi
M
M
Shirai
H
H
Sato
K
K
Matsuda
J
J
Atsumi
G
G
Ishida
N
N
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D006579:Heterozygote; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D017395:Plasminogen Activator Inhibitor 1; D015534:Trans-Activators; D056926:CLOCK Proteins; C538944:Clock protein, mouse