Modulation of adipose tissue development by pharmacological inhibition of PAI-1.
| Autor: | Crandall DL; Cardiovascular and Metabolic Disease Research, Wyeth Research, N2265A, PO Box 42528, Philadelphia, PA 19101, USA. crandad@wyeth.com, Quinet EM, El Ayachi S, Hreha AL, Leik CE, Savio DA, Juhan-Vague I, Alessi MC |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2006 Oct; Vol. 26 (10), pp. 2209-15. Date of Electronic Publication: 2006 Jul 06. |
| DOI: | 10.1161/01.ATV.0000235605.51400.9d |
| Abstrakt: | 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-1 in 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. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|