on July 6, 2006
Published online before print July 6, 2006, doi: 10.1161/01.ATV.0000235605.51400.9d
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Submitted on April 28, 2006
Accepted on June 19, 2006
Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1
David L. Crandall *;
From Cardiovascular and Metabolic Disease Research (D.L.C., E.M.Q., A.L.H., C.E.L., D.A.S.), Wyeth Research, Philadelphia, Pa; Laboratoire d’Hematologie UMR Inserm 626 (S.E.A., I.J.-V., M.-C.A.), Faculte de Medecine, Marseille, France.
* To whom correspondence should be addressed. E-mail: crandad{at}wyeth.com.
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 leptins were also significantly reduced in drug-treated mice, and concentrations of PAI-039 associated with these physiological effects were near the in vitro IC50 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 • diabetes • obesity • PAI-1
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