doi: 10.1161/01.ATV.0000244018.24120.70
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Editorials |
A Role for Plasminogen Activator Inhibitor-1 in Obesity: From Pie to PAI?
From the General Clinical Research Center and Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City.
Correspondence to William G. Haynes, MBChB, MD, Divisions of Clinical Pharmacology and Cardiovascular Diseases, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail william-g-haynes{at}uiowa.edu
The regulation of fibrinolysis depends on the interaction of plasma fibrinolytic and anti-fibrinolytic proteins. Fibrinolysis depends on the enzymatic conversion of plasminogen to plasmin. This process is mediated by tissue-type and urokinase-type plasminogen activators (t & uPAs, respectively).
See page 2209
Plasma antifibrinolytic activity is primarily regulated by plasminogen-activator inhibitors (PAIs).1 Four PAIs have been described: PAIs-1 through 3 and protease nexin. Importantly, PAI-1 is the main antagonist of t & uPAs, accounting for approximately 60% of the inhibition of plasminogen activators. PAI-2 mostly inhibits urokinase plasminogen activator (uPA), whereas protease nexin antagonizes plasmin, thrombin, and uPA. The antifibrinolytic activity of PAI-3 is uncertain. These molecules and others are also collectively known as serine protease inhibitors or "serpins".
PAI-1 is a single chain 45-kDa glycoprotein that contains from 379 to 381 amino acids. Endothelial and vascular smooth muscle cells are presumably the main sources of PAI-1 but other cells, such as platelets, hepatocytes, mesangial cells, fibroblasts, monocytes, macrophages, adipocytes, and stromal cells permeating the adipose tissue, have also been shown to secrete the serpin. The gene for PAI-1 is located on chromosome 7q21.3-q22, and its expression is mainly regulated at the transcriptional level through the action of several hormones [eg, renin-angiotensin-aldostrerone system (RAAS)], cytokines [eg, tumor necrosis factor (TNF) 
], lipoproteins (eg, VLDL), glucose, and endotoxin.1
Polymorphisms that influence PAI-1 gene expression have been described. The single 4/5 guanine polymorphism (4G/5G) in the promoter region of PAI-1 gene is widespread and has been associated with variable plasma PAI-1 activity and antigen levels.1 Indeed, plasma expression of PAI-1 antigen and activity are augmented in homozygous subjects for the 4G allele but decreased in 5G allele homozygous. This polymorphism may have important implications for human cardiovascular disease as suggested by case–control studies showing a higher prevalence of the 4G allele, coupled with high circulating PAI-1 in young patients with myocardial infarction.2
Beyond its function as an antifibrinolytic molecule, PAI-1 participates in poorly understood pleiotropic processes such as tumorigenesis, angiogenesis, wound healing, ovulation, and embryogenesis. There is also increasing evidence that PAI-1–dependent mechanisms may contribute to the pathogenesis of insulin resistance and type 2 diabetes mellitus. For example, in the IRAS study (Insulin Resistance Atherosclerosis Study, a longitudinal cohort of 1047 subjects followed for 5 years), PAI-1 was a strong predictor for the development of diabetes mellitus, even after adjusting for adiposity, body fat distribution, and insulin sensitivity.3 This link between PAI-1 and future risk of diabetes increased interest in the role of adipocyte-derived PAI-1 and its "pleiotropic" actions on insulin sensitivity and adipocyte biology.
Indeed, visceral and subcutaneous adipose tissue PAI-1 mRNA expression are positively correlated with BMI in severe obesity (r=0.043/0.56, respectively).4 Corroborating these results, BMI and plasma PAI-1 activity/antigen are positively and moderately associated (r=0.039/0.36, respectively), at least in mildly hypertensive men.5 Moreover, weight reduction substantially reduces plasma PAI-1 in obese humans.6 These observational findings are in line with results correlating plasma PAI-1 with ex vivo PAI-1 secretion from adipose tissue harvested during abdominoplasty.7 Furthermore, ex vivo secretion of PAI-1 from omental adipose tissue is greater than that from subcutaneous adipocytes.8 Thus, increased omental fat secretion of PAI-1 could potentially contribute to the augmented atherothrombotic risk of human central obesity. In addition to these data demonstrating adipocyte generation of PAI-1, there are now intriguing data suggesting a direct effect of PAI-1 on adipocytes.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Crandall et al show that pharmacological inhibition of PAI-1, by a novel small molecule (PAI-0039), reduces human preadipocyte differentiation and attenuates dietary fat-induced obesity in C57BL/6 mice.9 In vitro, PAI-039 blocked both PAI-1 antigen and leptin secretion by adipocytes. Intriguingly, PAI-039 inhibited differentiation of human preadipocytes, and reduced the size and number of lipid containing vesicles in adipocytes. Importantly, the authors also demonstrated in vivo an effect of PAI-039 to dose-dependently reduce body weight, epididymal (visceral) adipose tissue, adipocyte volume, and circulating plasma active PAI-1. There was also evidence of improvement in metabolic syndrome because plasma glucose, triglycerides, insulin resistance, and leptin were significantly reduced by PAI-039. This article provides important evidence for an autocrine role of PAI-1 in adipocyte differentiation and lipid accumulation, though the mechanisms of this effect remain unclear.
The authors assessed the in vivo effects of PAI-039 in animals that were pair-fed to maintain near identical calorie intake. The fact that body weight, adiposity, and insulin resistance decreased after PAI-039 in the face of unchanged food intake suggests that PAI-1 inhibition alters metabolic rate (perhaps through changes in uncoupling protein mediated thermogenesis; see below). However, because the authors did not also test the effects of PAI-039 in free-fed animals it is impossible to know the effects of PAI-1 inhibition on appetite. For example, it is possible that decreased leptin concentrations after PAI-039 may lead to increased appetite and food intake. One related question is whether the improvement in metabolic syndrome is solely attributable to a decrease in body fat or whether PAI inhibition (directly, or indirectly through effects on PPAR or TNF) influences insulin sensitivity and triglyceride rich lipoprotein production or clearance. More sophisticated pair feeding studies (ie, "clamping" body weight by adjusting diet) would help to answer this question.
The in vitro results of Crandall et al contrast with one recent article which suggested that PAI-1 inhibits adipocyte differentiation likely through increased PPAR
activity.10 However, the in vivo demonstration of reduced adipocyte differentiation using PAI-039 by Crandall et al, along with other in vivo studies of genetically modified mice, suggests that the overall effect of PAI-1 is to promote adipocyte differentiation and obesity.
Experimental models of PAI-1 genetic abrogation generally support a role for PAI-1 in adipocyte development and growth. Schafer et al demonstrated that leptin-deficient obese, diabetic ob/ob mice lacking PAI-1 are less obese and have lower fat mass than obese ob/ob mice with intact PAI-1.11 Deficiency of PAI-1 also decreased plasma glucose and insulin levels, consistent with prevention of insulin resistance. Importantly, adipose tissue expression of TNF mRNA and protein were substantially reduced in PAI-1 deficient ob/ob mice. Insulin resistance has been consistently associated with increased inflammation. Therefore, improvement of metabolic parameters could have been attributable to reduced TNF. One problem with this study is the use of a leptin-deficient mouse as a model for obesity (because leptin has diverse metabolic and vascular actions in addition to regulation of body weight).
However, Ma et al also demonstrated a reduction of fat mass in 4-week-old PAI-1–deficient mice with a C57BL/6J background fed a high fat diet (ie, 58% of calories as fat) for 12 weeks.12 Increased resting metabolic rate, energy expenditure and body temperature contributed to relative resistance of PAI-1–deficient mice to dietary-induced obesity. In concordance with the findings of Crandall et al, PAI-1–deficient mice exhibited substantially lower serum concentrations of leptin as compared with controls. Importantly, contrasting with wild-type animals, PAI-1–deficient mice preserved PPAR and adiponectin mRNA expression despite high fat diet. Also of notice is that the expression of skeletal muscle uncoupling protein type 2 (UCP2) was increased in PAI-1–deficient mice, which is compatible with increased energy expenditure. It is possible that PAI-1 may not interact directly with UCP2. Instead, preserved PPAR expression in PAI-1–deficient mice may contribute to increased UCP2 expression.13
In contrast with the other studies, Morange et al did not observe reduced body weight in 10-week-old PAI-1–deficient mice on a mixed genetic background (ie, 81% C57BL/6 and 19%129SV), fed with high fat diet (ie, 42% of calories as fat) for 17 weeks.14 Indeed, PAI-1–deficient animals gained weight faster than control mice, although the final body weight and gonadal, retroperitoneal, and subcutaneous fat mass did not differ between PAI-1–deficient and control mice. Another study from these investigators showed that adipocyte-specific overexpression of PAI-1 attenuated diet-induced obesity in mice fed a diet containing 42% fat as calories.15 The striking differences between some studies may be due to differences in age, fat composition of diet, and genetic backgrounds.
What are the mechanisms underlying the effects of PAI-1 deficiency or inhibition on adipocyte differentiation and growth? Crandall et al suggest three possible ways in which PAI-1 may influence adipocyte biology. First, PAI-1 inactivation by PAI-039 may stimulate migration of preadipocytes that would in turn prevent their full differentiation into mature adipocytes. Second, PAI-1 inhibition may block angiogenesis (perhaps through reduction of leptin secretion) that would impair vascularization and thus growth of adipose tissue. Third, PAI-1 may affect adipose tissue growth by altering receptor-dependent transport of lipids into the cell.
However, we would like to highlight another potential explanation for the effects of PAI-039, namely interaction of PAI-1 with inflammatory mediators and the nuclear receptor PPAR (Figure). It has been known for some time that both TNF and transforming growth factor (TGF) ß upregulate PAI-1.16 Because obesity is associated with increased adipocyte expression of TNF and TGFß, these cytokines could be important contributors to the generation of adipocyte-derived PAI-1 in obesity.17 Interestingly, PPAR expression is downregulated by both PAI-1 and TNF.10,18 In addition, knockdown of PAI-1 prevents TNF-induced inhibition of adipocyte glucose uptake, suggesting that PAI-1 mediates the development of inflammation-induced insulin resistance.10 Together, these observations suggest that blockade of PAI-1 may prevent obesity and insulin resistance by preventing inflammation and enhancing activation of PPAR (Figure).
|
Given that a preponderance of studies using genetic or pharmacological interference with PAI-1 show decreased adipocyte differentiation, and prevent obesity, it is tempting to pursue PAI-1 as a target for treatment of obesity or metabolic syndrome. However, pharmacological interference with adipocyte differentiation should be carried out with caution because of the potential for disruption of lipid metabolism. Indeed, extreme impairment of adipocyte differentiation as occurring in animal and human lipodystrophy syndromes causes toxic accumulation of lipids in nonadipose tissues. Human lipodystrophy is characterized by skeletal muscle steatosis, hepatic statosis, pancreatic and renal dysfunction attributable to lipid infiltration. Presumably, the lipotoxic effect of lipid infiltration of the pancreas and skeletal muscle are important factors in the pathogenesis of lipodystrophy-related diabetes. Cardiac dysfunction has also been correlated with myocardial lipid accumulation in leptin-resistant Zucker obese fa/fa rats.19
We now have increasing evidence supporting an autocrine role for adipocyte PAI-1 in promotion of adipocyte differentiation and lipid accumulation. It is plausible that PAI-1 inhibitors might delay adipocyte differentiation, thus reducing fat mass, improving glucose and lipoprotein metabolism, and reducing inflammation. As Danforth insightfully reminds us, 30 years ago Knittle and Hirsch suggested that too many adipocytes predisposed to obesity.20 Today, the concept that too few adipocytes predispose to insulin resistance gains ground. Future studies with PAI-1 inhibitors should include a detailed description of their effects on appetite, adipocyte biology, insulin and lipid metabolism, and also test for potential lipotoxic effects of ectopic lipid deposition in non-adipose tissues.
 |
Acknowledgments |
|---|
Sources of Funding
Dr Correia is partly supported by the State University of Rio de Janeiro, Brazil. Dr Haynes is supported by grants from the National Institutes of Health (NHLBI: HL-14388, HL55006, HL58972; NCRR General Clinical Research Centers program: RR00059).
Disclosures
None.
|
References |
|---|
 Top References |
|---|
- Feinbloom D, Bauer KA. Assessment of hemostatic risk factors in predicting arterial thrombotic events. Arterioscler Thromb Vasc Biol. 2005; 25: 2043–2053.
[Abstract/Free Full Text] - Eriksson P, Kallin B, van ’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995; 92: 1851–1855.
[Abstract/Free Full Text] - Festa A, D’Agostino R Jr., Tracy RP, Haffner SM; Insulin Resistance Atherosclerosis Study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes. 2002; 51: 1131–1137.
[Abstract/Free Full Text] - Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I. Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes. 2000; 49: 1374–1380.[Abstract]
- Skurk T, Lee YM, Nicuta-Rolfs TO, Haastert B, Wirth A, Hauner H. Effect of the angiotensin II receptor blocker candesartan on fibrinolysis in patients with mild hypertension. Diabetes Obes Metab. 2004; 6: 56–62.[CrossRef][Medline] [Order article via Infotrieve]
- Mavri A, Alessi MC, Bastelica D, Geel-Georgelin O, Fina F, Sentocnik JT, Stegnar M, Juhan-Vague I. Subcutaneous abdominal, but not femoral fat expression of plasminogen activator inhibitor-1 (PAI-1) is related to plasma PAI-1 levels and insulin resistance and decreases after weight loss. Diabetologia. 2001; 44: 2025–2031.[CrossRef][Medline] [Order article via Infotrieve]
- Morange PE, Alessi MC, Verdier M, Casanova D, Magalon G, Juhan-Vague I. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol. 1999; 19: 1361–1365.
[Abstract/Free Full Text] - Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes. 1997; 46: 860–867.[Abstract]
- Crandall DL, Quinet EM, El Ayachi S, Hreha AL, Leik CE, Savio DA, Juhan-Vague I, Alessi MC. Modulation of adipose tissue development by pharmacological inhibition of PAI-1. Arterioscler Thromb Vasc Biol. 2006; 26: 2209–2215.[CrossRef][Medline] [Order article via Infotrieve]
- Liang X, Kanjanabuch T, Mao SL, Hao CM, Tang YW, Declerck PJ, Hasty AH, Wasserman DH, Fogo AB, Ma LJ. Plasminogen activator inhibitor-1 modulates adipocyte differentiation. Am J Physiol Endocrinol Metab. 2006; 290: E103–E113.
[Abstract/Free Full Text] - Schafer K, Fujisawa K, Konstantinides S, Loskutoff DJ. Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J. 2001; 15: 1840–1842.
[Free Full Text] - Ma LJ, Mao SL, Taylor KL, Kanjanabuch T, Guan Y, Zhang Y, Brown NJ, Swift LL, McGuinness OP, Wasserman DH, Vaughan DE, Fogo AB. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes. 2004; 53: 336–346.
[Abstract/Free Full Text] - Shimokawa T, Kato M, Watanabe Y, Hirayama R, Kurosaki E, Shikama H, Hashimoto S. In vivo effects of pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice. Biochem Biophys Res Commun. 1998; 251: 374–378.[CrossRef][Medline] [Order article via Infotrieve]
- Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol. 2000; 20: 1150–1154.
[Abstract/Free Full Text] - Lijnen HR, Maquoi E, Morange P, Voros G, Van Hoef B, Kopp F, Collen D, Juhan-Vague I, Alessi MC. Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 2003; 20: 78–84.
- Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest. 1991; 88: 1346–1353.[Medline] [Order article via Infotrieve]
- Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord. 2004; 28: 1357–1364.[CrossRef][Medline] [Order article via Infotrieve]
- Zhang B, Berger J, Hu E, Szalkowski D, White-Carrington S, Spiegelman BM, Moller DE. Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. Mol Endocrinol. 1996; 10 (11): 1457–66.[Abstract]
- Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000; 97: 1784–1789.
[Abstract/Free Full Text] - Danforth E Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet. 2000; 26: 13.[Medline] [Order article via Infotrieve]
Related Article:
- Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1
- David L. Crandall, Elaine M. Quinet, Soulaf El Ayachi, Amy L. Hreha, Courtney E. Leik, Dawn A. Savio, Irene Juhan-Vague, and Marie-Christine Alessi
Arterioscler. Thromb. Vasc. Biol. 2006 26: 2209-2215.[Abstract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  S. M. Nelson, N. Sattar, D. J. Freeman, J. D. Walker, and R. S. Lindsay Inflammation and Endothelial Activation Is Evident at Birth in Offspring of Mothers With Type 1 Diabetes Diabetes, November 1, 2007; 56(11): 2697 - 2704. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||