In adipose tissue from both obese mice and humans, plasminogen activator inhibitor 1 (PAI-1) expression has been reported to be upregulated to levels of increased plasma PAI-1. This elevated expression has been shown to be partly controlled by tumor necrosis factor (TNF)-␣ in mice. In humans, increased PAI-1 expression is associated with insulin resistance characterized by visceral fat accumulation. Therefore, the aim of this study was to investigate the expression pattern of PAI-1 and TNF-␣ (antigen and mRNA) in visceral human adipose fat in comparison with subcutaneous (SC) fat. Because transforming growth factor (TGF)-␤ 1 is a potent inducer of PAI-1 synthesis and has been shown to influence adipocyte metabolism, this work was extended to TGF-␤ 1 quantification. A total of 32 obese individuals (BMI 42 ± 6.8 kg/m 2 ) were investigated. Freshly collected visceral adipose tissue did not exhibit a higher content of PAI-1 or TGF-␤ 1 than did SC tissue. Although most of the TNF-␣ values were at the detection limit of the methods, TNF-␣ antigen was 3-fold higher and TNF-␣ mRNA was 1.2-fold higher in visceral fat. The levels of tissue TGF-␤ 1 antigen correlated well with those of PAI-1 antigen, regardless of the fat depot studied (SC tissue: n = 21, r = 0.72, P = 0.0006; visceral tissue: n = 20, r = 0.49, P < 0.03), and they were both significantly associated with BMI. Conversely, no relationship was observed between the levels of TNF-␣ and PAI-1 or TNF-␣ and BMI. Tissue PAI-1 levels were also significantly correlated with those of circulating PAI-1. These results describe, in severe obesity, a proportional increase in tissue PAI-1 and TGF-␤ 1 in visceral and SC tissues. This increased PAI-1 expression could be the result of tissue cytokine disturbances, such as elevated TGF-␤ 1 expression.

Objective-Because obesity and insulin resistance (IR) are strongly associated with liver steatosis (LS), we investigated the relation between the degree of LS and plasminogen activator inhibitor-1 (PAI-1) in ob/ob mice, in C57/BL6 mice with alcoholic LS, and in severely obese humans. Methods and Results-In both mouse models, plasma PAI-1 levels were associated with PAI-1 expression in the liver and with the degree of LS. Liver PAI-1 antigen was associated with the tumor necrosis factor receptor-II (TNFRII) antigen, whereas association with TNF antigen content was found in ob/ob mice only. No significant correlation between plasma PAI-1 and PAI-1 expression in adipose tissue of ob/ob mice was observed. Furthermore, the relation between plasma PAI-1 levels and body weight was positive in ob/ob mice but negative in C57/BL6 mice (both PϽ0.001). In humans, PAI-1 levels were correlated with the degree of LS, and 26% of plasma PAI-1 activity was independently explained by LS and serum insulin levels. Conclusions-Plasma PAI-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue. In steatotic liver, PAI-1 antigen content is associated with those of TNF and TNFRII. Therefore, we suggest that TNF pathway dysregulation in LS could be involved in increased plasma PAI-1 in obesity with IR. Key Words: liver steatosis Ⅲ PAI-1 Ⅲ adipose tissue Ⅲ insulin resistance P lasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of fibrinolysis. PAI-1 modulates the development of atherosclerosis in mice, 1,2 and an elevated plasma PAI-1 concentration is predictive for myocardial infarction in humans. 3,4 Interestingly, the predictive value of circulating PAI-1 levels is highly dependent on the insulin resistance syndrome. 4,5 Despite several efforts in the last few years, the mechanism of increased plasma PAI-1 concentration in insulin resistance associated with android obesity is not completely understood. PAI-1 is expressed in murine as well as in human adipose tissue, 6 -9 and its expression in adipose tissue is correlated positively with body mass index (BMI). 9 -11 Human visceral adipose tissue expresses more PAI-1 than does subcutaneous abdominal adipose tissue. 7,12 Furthermore, PAI-1 expression in only abdominal, but not in femoral subcutaneous adipose tissue, is associated with the features of insulin resistance. 11 Therefore, it has been postulated that in the insulin resistance syndrome with central obesity, abdominal adipose tissue is an important source of plasma PAI-1. Of note, an increase in plasma PAI-1 is also observed in lipodystrophy associated with antiretroviral treatment in HIV patients. These patients typically have prominent, peripheral fat wasting and maintained or decreased visceral fat depots and are insulin resistant. Interestingly, the difference in plasma PAI-1 levels between HIV patients and healthy controls was independent of HIV infection status and was not affected after adjustment for visceral fat estimation but was rather explained by...

Abstract-Elevated plasma plasminogen activator inhibitor (PAI)-1 observed during insulin resistance has been connected with an excessive PAI-1 adipose tissue secretion mainly by visceral fat. Our aim was to compare the localization of PAI-1 in human visceral and subcutaneous fats. PAI-1 secretion was also investigated in vitro during human adipocyte differentiation. PAI-1 antigen and mRNA were localized in the stromal area of the tissue and were also present in a few CD14-positive monocytes, in direct contact with adipocytes. In addition, in subcutaneous tissue, PAI-1 mRNA contents, determined by using real-time polymerase chain reaction, were higher in the stromal fraction than in the adipocyte fraction. PAI-1 mRNA-positive cells were 5-fold more frequent in the visceral area than in the subcutaneous stromal area (Pϭ0.004). Such a difference was also observed for PAI-1 mRNA content between both whole adipose tissues. In contrast to leptin, during adipocyte differentiation, PAI-1 secretion did not follow adipocyte maturation. In situ hybridization in culture did not reveal PAI-1 mRNA in lipid-filled cells. Our results demonstrate that PAI-1 production is mainly due to stromal cells, which were more numerous in the visceral than in the subcutaneous depot. These results could explain the strong relationship observed between circulating PAI-1 levels and the accumulation of visceral fat.

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A study was performed to attempt to modify the healing response to severe oesophageal corrosive burns to prevent complications. The study was performed on four groups each of 15 Wistar rats: a control group, an untreated group and groups given epidermal growth factor (EGF) alone or EGF for 5 days and interferon (IFN) gamma from the sixth to 20th day. In the last three groups an oesophageal lesion was induced with 2.5 mol l-1 sodium hydroxide solution. The efficacy of treatment was assessed on days 2, 5 and 20 by measurement of weight gain, oesophageal internal lumen, stenosis index (wall thickness: lumen diameter) and collagen production. On day 5, collagen synthesis was significantly (P < 0.05) higher in rats given EGF than in the untreated group. On day 20, no significant difference was seen in weight gain between the control rats and either treated group and stenoses were present in all untreated rats and in none of the treated group. The stenosis index on day 20 was lower in the groups given EGF and EGF-IFN-gamma than in untreated rats (P < 0.05) and collagen production was significantly (P < 0.05) lower in the group given EGF and IFN-gamma than in the other animals. The sequential use of EGF and IFN-gamma significantly reduced the frequency of residual stenosis.

T he prevalence of obesity is steadily increasing so much, so that obesity has become a pandemic in developed and developing nations. 1 The increased risk of morbidity and mortality and more particularly of atherosclerotic cardiovascular disease associated with obesity and insulin-resistant states is of great public health concern.2,3 Each 5 kg/m 2 increase above a body mass index (BMI) of 25 kg/m 2 results in a 40% increase in cardiovascular mortality.3 Dyslipidemia is a prominent feature of obesity and insulin-resistant states. 4 The typical dyslipidemia associated with these conditions is mainly characterized by elevated plasma triglyceride concentration, low high-density lipoprotein-cholesterol (HDL-C) level, increased proportion of small and dense low-density lipoprotein (LDL), and postprandial hyperlipidemia.4,5 These abnormalities contribute to the high residual cardiovascular risk observed in obesity and insulin-resistant states, even if low LDL-C levels are achieved by statin treatment.6,7 The pathophysiology of this dyslipidemia is widely explained by the blood accumulation of triglyceride-rich lipoproteins (TRL) from the liver (apolipoprotein [apo]B-100-containing very low-density lipoprotein [VLDL]) and the intestine (apoB-48-containing chylomicrons). This accumulation has been attributed to the © 2014 American Heart Association, Inc. Objective-The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. Approach and Results-Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRLapoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of pati...

SummaryPlasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFβ1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA).Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFβ1) whereas in adipose tissue only PAI-1, t-PA and TGFβ1 antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFβ1, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively.Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.Abbreviations: act: activity; ag: antigen; BMI: Body mass index; IL-6: Interleukin-6; PAI-1: plasminogen activator inhibitor type 1; TGFβ1: Transforming Growth Factor beta 1; TNF: Tumor Necrosis Factor alpha; TNFRSF1A and 1B: Tumor Necrosis Factor receptor superfamilly 1A and 1B (TNFRI and II respectively); t-PA: tissue type plasminogen activator; u-PA: urokinase type plasminogen activator

Portal vein thrombosis can occur after laparoscopic operations. This complication has not been yet reported after laparoscopic sleeve gastrectomy. We report the case of a patient who presented mild abdominal pains 2 weeks after a laparoscopic sleeve gastrectomy achieved to cure morbid obesity. Computed tomography led to the diagnosis of portal vein thrombosis bound to a genetic disorder due to heterozygote Leiden 2 factor which impaired coagulation. Recommendations for post-surgical follow-up are discussed.