De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE. Macrophage TNF-␣ contributes to insulin resistance and hepatic steatosis in diet-induced obesity.
articles integrative Physiologydiabetes, expression and regulation in adipose tissues and adipocytes were investigated. Our data indicate that sEH is expressed in adipocytes, expression increases during adipogenesis and is specifically induced in adipose tissue by PPARγ agonists. Methods and Procedures animals for proteomic analysisAdult (6-week-old) male C57BL/6J mice were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice were housed in a pathogen-free barrier facility (12 h light/12 h dark cycle). For the proteomic analysis, five animals received a regular, standard fat diet (SFD) for 20 weeks (diet 5001; LabDiet, Richmond, IN) in which 12% of the calories were derived from fat and five animals received a high-fat diet (HFD) for 20 weeks (diet TD 88137; Harlan Teklad, Madison, WI) in which 42% of total calories were derived from fat. Mice were weighed every 2 weeks. At the beginning and the end of the feeding period, body composition was determined using a Minispec model mq 7.5 (7.5 mHz) (Bruker Optics, Billerica, MA) and the animals were killed under anesthesia with isoflurane (Baxter, Deerfield, IL). The epididymal fat pads, livers, and kidneys were harvested and weighed; one part of the tissues was snap-frozen in liquid nitrogen and stored at −80 °C for further analysis while another part was fixed in 10% formalin for immunohistochemistry. To evaluate expression of sEH in different adipose depots, 6-week-old C57BL/6J mice were fed the HFD or SFD for 13 weeks; epididymal fat pads, subcutaneous fat pads, perirenal fat pads, and pericardial fat pads were collected and stored at −80 °C. These studies were initiated at the Vanderbilt
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.Plasminogen activator inhibitor type-1 (PAI-1) 2 is the principal inhibitor of tissue-type plasminogen activator and urokinase-type plasminogen activator and, therefore, is a key regulatory protein of the plasminogen/pro-matrix metalloproteinase system (for review, see Ref. 1). As such, PAI-1 is involved in many overlapping processes as fibrinolysis, activation of promatrix metalloproteinases, cell migration, angiogenesis, and tissue remodeling (for review, see Ref.2). Plasma PAI-1 likely represents synthesis in a number of tissues, including vascular endothelial cells (3), the liver (4), smooth muscle cells (5), and adipocytes (6).There is substantial evidence linking PAI-1 with obesity and insulin resistance. In humans, the visceral fat mass correlates with plasma PAI-1. Conversely, weight loss promotes a decrease in plasma PAI-1 levels, which predictably rebound when weight is regained (7,8). PAI-1 levels fall and fibrinolytic activity improves in patients undergoing weight reduction surgery (9, 10). Additional evidence supporting the relationship between PAI-1 and obesity has been observed in experimental studies using genetically modified mice. PAI-1 deficiency reduces adiposity and improves the metabolic profile in genetically obese mice (11). Similarly, PAI-1 deficiency attenuates nutritionally induced obesity and insulin resistance in C57BL/6 mice (12). However, the relationship between PAI-1 and obesity is not strictly linear, and the site of PAI-1 expression and the genetic background of the mice influence the response to high caloric intake. For example, transgenic mice overexpressing PAI-1 in fat gain less weight than their wild-type counterparts (13), and PAI-1 deficient mic...
At present, thrombolytic agents represent the only direct way of augmenting fibrinolytic activity in humans. While these agents are proven to be efficacious in the treatment of acute thrombotic events, they are not a viable option for long-term administration. There are numerous drugs available that indirectly to increase fibrinolytic activity by reducing plasma levels of plasminogen activator inhibitor-1 (PAI-1), including ACE inhibitors, insulin-sensitizing agents, and hormone replacement therapy in women. At present, efforts are underway to develop and test synthetic, selective PAI-1 antagonists. The potential applications of PAI-1 antagonists include thrombotic disorders (arterial and venous), amyloidosis, obesity, polycystic ovarian syndrome, and perhaps even type 2 diabetes mellitus. The availability of specific PAI-1 antagonists promises to expand the limits of understanding the role the fibrinolytic system plays in human disease and break through the current confines of therapeutic options that can effectively restore and augment the activity of the fibrinolytic system.
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