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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2209.)
© 2006 American Heart Association, Inc.

Vascular Biology

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; Marie-Christine Alessi

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.

Correspondence to David L. Crandall, Wyeth Research, N2265A, PO Box 42528, Philadelphia, PA 19101. 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 leptin 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.

Pharmacological inhibition of PAI-1 was achieved in vitro and in vivo, resulting in effects on adipose tissue differentiation. PAI-1 inhibition may be beneficial in those diseases associated with increased adipose tissue mass, including diabetes and obesity.

Key Words: adipocyte • diabetes • obesity • PAI-1

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A Role for Plasminogen Activator Inhibitor-1 in Obesity: From Pie to PAI?

Marcelo L.G. Correia and William G. Haynes
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