Objective-The effect of a novel small molecule plasminogen activator inhibitor (PAI-1) inhibitor on adipose tissue physiology was investigated. Methods and Results-In human preadipocyte cultures, PAI-039 inhibited both basal and glucose-stimulated increases in active PAI-1 antigen, yet had no effect on PAI-1 mRNA, suggesting a direct inactivation of PAI-1. Differentiation of human preadipocytes to adipocytes was associated with leptin synthesis, which was significantly reduced in the presence of PAI-039, together with an atypical adipocyte morphology characterized by a reduction in the size and number of lipid containing vesicles. In a model of diet-induced obesity, pair-fed C57 Bl/6 mice administered PAI-039 in a high-fat diet exhibited a dose-dependent reduction in body weight, epididymal adipose tissue weight, adipocyte volume, and circulating plasma active PAI-1. Plasma glucose, triglycerides, and leptin were also significantly reduced in drug-treated mice, and concentrations of PAI-039 associated with these physiological effects were near the in vitro IC 50 for the inhibition of PAI-1. Conclusions-Our results indicate that a small molecule inactivator of PAI-1 can neutralize glucose-stimulated increases in PAI-1in human preadipocyte cultures, reduce adipocyte differentiation, and prevent the development of diet-induced obesity. These data suggest the pharmacological inhibition of PAI-1 could be beneficial in diseases associated with expansion of adipose tissue mass. Key Words: adipocyte Ⅲ diabetes Ⅲ obesity Ⅲ PAI-1 T ype 2 diabetes accounts for Ͼ90% of diabetes globally and continues to increase at epidemic proportions. 1 Cardiovascular morbidity is a major burden in patients with type 2 diabetes, and their risk of death from cardiovascular disease is increased significantly over nondiabetic subjects. 2 Aggressive treatment of both diabetes and cardiovascular disease in this population through a combination of diet, exercise, and pharmacological therapy has recently been reported to result in a 20% reduction in cardiovascular events, 3 whereas treatment of hyperglycemia alone produces less benefit. 4 Taken together, a significant number of diabetics continue to exhibit vascular disease that is refractory to current therapy. See page 2183Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), 5 and is physiologically involved in both thrombosis and atherosclerosis. 6 PAI-1 is found in the circulation of healthy individuals at low concentrations, and although it has a potential regulatory role in tumorigenesis, inflammation, and thrombosis, 7 PAI-1 is both elevated in the plasma of type 2 diabetic patients and is an important predictor of the onset of the disease. 8 The discovery that PAI-1 is synthesized by adipose tissue suggested that it represents a possible causal link between obesity and the increased atherothrombosis observed in diabetics. This hypothesis is further supported by additional studies establi...

The circular muscle from the human colon is a target tissue for glicentin and GLP-1. Whereas glicentin is a long-life digestive hormone which would contribute to segmental contraction, the biological activity of GLP-1 remains unknown on this tissue. On the digestive smooth muscle, exendin-(9-39) behaved as an antagonist for two members of the glucagon-receptor family, GLP-1 and glicentin.

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