CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression

J Thromb Haemost. 2006 Aug;4(8):1774-80. doi: 10.1111/j.1538-7836.2006.02032.x.

Abstract

Background: An increased level of obesity-induced plasma plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular disease.

Aim: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • CLOCK Proteins
  • Circadian Rhythm
  • Fibrinolysis*
  • Gene Expression Regulation*
  • Heterozygote
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Obese
  • Obesity / genetics*
  • Plasminogen Activator Inhibitor 1 / biosynthesis*
  • Time Factors
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*

Substances

  • Plasminogen Activator Inhibitor 1
  • Trans-Activators
  • CLOCK Proteins
  • Clock protein, mouse