PROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-α MEDIATES HIGH-FAT, DIET-ENHANCED DAILY OSCILLATION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 ACTIVITY IN MICE

Introduction: Elevated plasminogen activator inhibitor-1 (PAI-1) is associated with obesity, but there is controversy whether PAI-1 causes or is a consequence of obesity. We sought to determine whether targeted PAI-1 inhibition with a novel small molecule antagonist (TM5441) alters the development of obesity and/or obesity-induced vascular dysfunction in a diet-induced obesity model. Methods and Results: C57BL/6J mice were fed control, high fat diet (HFD), or high fat diet with TM5441 (HFD+TM5441) for 12 weeks. The HFD had marked weight gain (77±5%) as compared with control (32±2%). TM5441 significantly attenuated weight gain (49±8%, p=0.0075, Figure). HFD-induced hepatic triglyceride accumulation was attenuated by TM5441 (116±31 vs. 76±35 mg trig/g liver, p=0.03). Energy expenditure was reduced in the HFD compared to control (11.1±0.4 vs. 12.9±0.4 kcal/h/kg, p=0.005). However, HFD+TM5441 maintained a level of energy expenditure that was similar to control (13.2±0.6 kcal/h/kg, p=NS). The HFD group demonstrated higher systolic and diastolic blood pressure (141±3; 112±3 mm Hg) compared with control (122±7, 94±8; P<0.05 for both), while administration of TM5441 prevented diet-associated increase (120±6; 93±7 mm Hg, p=NS compared to control) at week 12. Pressure myography of mesenteric arteries in the HFD showed a significant rightward shift in the constrictor response to phenylephrine as compared to control (EC50: 14.5uM vs. 25.1uM, p=0.002). The HFD+TM5441 was similar to control (p=NS). Conclusions: Inhibition of PAI-1 with TM5441 attenuates weight gain, enhances energy expenditure, and prevents obesity-related vascular dysfunction in a murine model of obesity.

Download Full-text

Obesity and Breast Cancer: The Roles of Peroxisome Proliferator-Activated Receptor-γand Plasminogen Activator Inhibitor-1

PPAR Research ◽

10.1155/2009/345320 ◽

2009 ◽

Vol 2009 ◽

pp. 1-13 ◽

Cited By ~ 28

Author(s):

Jennifer C. Carter ◽

Frank C. Church

Keyword(s):

Breast Cancer ◽

Plasminogen Activator ◽

High Fat Diet ◽

Plasminogen Activator Inhibitor ◽

Peroxisome Proliferator ◽

High Fat ◽

Plasminogen Activator Inhibitor 1 ◽

Peroxisome Proliferator Activated Receptor ◽

Activator Inhibitor ◽

Pai 1

Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer. As a key mediator of adipogenesis and regulator of adipokine production, peroxisome proliferator-activated receptor-γ(PPAR-γ) is involved in PAI-1 expression from adipose tissue. We summarize the current knowledge linking PPAR-γand PAI-1 expression to high-fat diet and obesity in the risk of breast cancer.

Download Full-text

Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice

Thrombosis and Haemostasis ◽

10.1160/th05-01-0043 ◽

2005 ◽

Vol 93 (05) ◽

pp. 816-819 ◽

Cited By ~ 16

Author(s):

Roger Lijnen

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Plasminogen Activator ◽

High Fat Diet ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

High Fat ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator. Recent studies in murine models have yielded apparently conflicting data on a potential role of PAI-1 in adipose tissue development and obesity. To reinvestigate this issue, we have rederived PAI-1 deficient (PAI-1-/-) and wild-type (WT) mice and generated true littermates in a 81.25% C57Bl/6: 18.75% 129 SV genetic background. Male 5-week-old PAI-1-/- and WT mice were kept on a high fat diet (20.1 kJ/g) for 15 weeks. Body weight gain was comparable for both genotypes, and at the time of sacrifice total body weights (39 ± 1.1 versus 41 ± 1.2 g) as well as the weights of subcutaneous (SC, 1,520 ± 110 versus 1,480 ± 110 mg) adipose tissue were not significantly different. In contrast, the gonadal (GON, 1,900 ± 43 versus 1,510 ± 86 mg, p < 0.005) tissue mass was larger in PAI-1-/- mice. Plasma levels of insulin, leptin, glucose, triglycerides, total, HDL and LDL cholesterol were comparable for both genotypes. Immunohisto-chemical analysis of SC and GON adipose tissues did not reveal differences in adipocyte size or number between both genotypes, whereas blood vessel density was also comparable for GON fat but lower in SC fat of WT mice. Thus, this study in littermate mice on high fat diet did not reveal an effect of PAI-1 deficiency on body weight, and a differential effect on SC and GON adipose tissue.

Download Full-text