scholarly journals A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice

2016 ◽  
Vol 173 (17) ◽  
pp. 2622-2632 ◽  
Author(s):  
Lingjuan Piao ◽  
Inji Jung ◽  
Joo Young Huh ◽  
Toshio Miyata ◽  
Hunjoo Ha
Keyword(s):  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Diet Induced Obesity ◽  
Activator Inhibitor

scholarly journals Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1

2008 ◽  
Vol 283 (20) ◽  
pp. 13538-13548 ◽  
Author(s):  
Charmi Shah ◽  
Guang Yang ◽  
Ian Lee ◽  
Jacek Bielawski ◽  
Yusuf A. Hannun ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor

Abstract 179: Targeted Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Weight Gain and Prevents Vascular Dysfunction Following a High Fat Diet

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sadiya S Khan ◽  
Alexander Mackie ◽  
Lauren Beussink-Nelson ◽  
Christine E Kamide ◽  
Anne S Henkel ◽  
...  
Keyword(s):  
Weight Gain ◽  
Energy Expenditure ◽  
Plasminogen Activator ◽  
High Fat Diet ◽  
Vascular Dysfunction ◽  
Plasminogen Activator Inhibitor ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

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.

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

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-13 ◽  
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.

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

2005 ◽  
Vol 93 (05) ◽  
pp. 816-819 ◽  
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.

scholarly journals Bone Marrow Plasminogen Activator Inhibitor-1 Influences the Development of Obesity

2006 ◽  
Vol 281 (43) ◽  
pp. 32796-32805 ◽  
Author(s):  
Bart M. De Taeye ◽  
Tatiana Novitskaya ◽  
Linda Gleaves ◽  
Joseph W. Covington ◽  
Douglas E. Vaughan
Keyword(s):  
Bone Marrow ◽  
Plasminogen Activator ◽  
Visceral Fat ◽  
Primary Source ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Diet Induced Obesity ◽  
Activator Inhibitor ◽  
Pai 1

Plasma levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in obesity and correlate with body mass index. The increase in PAI-1 associated with obesity likely contributes to increased cardiovascular risk and may predict the development of type 2 diabetes mellitus. Although adipocytes are capable of synthesizing PAI-1, the bulk of evidence indicates that cells residing in the stromal fraction of visceral fat are the primary source of PAI-1. We hypothesized that bone marrow-derived PAI-1, e.g. derived from macrophages located in visceral fat, contributes to the development of diet-induced obesity. To test this hypothesis, male C57BL/6 wild-type mice and C57BL/6 PAI-1 deficient mice were transplanted with either PAI-1-/-, PAI-1+/-, or PAI-1+/+ bone marrow. The transplanted animals were subsequently fed a high fat diet for 24 weeks. Our findings show that only the complete absence of PAI-1 protects from the development of diet-induced obesity, whereas the absence of bone marrow-derived PAI-1 protects against expansion of the visceral fat mass. Remarkably, there is a link between the PAI-1 levels, the degree of inflammation in adipose tissue, and the development of obesity. Based on these findings we suggest that bone marrow-derived PAI-1 has an effect on the development of obesity through its effect on inflammation.

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