Modulation of adipose tissue development by pharmacological inhibition of PAI-1.
OBJECTIVE
The effect of a novel small molecule plasminogen activator inhibitor (PAI-1) inhibitor on adipose tissue physiology was investigated.


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.
Crandall
David L
DL
Cardiovascular and Metabolic Disease Research, Wyeth Research, N2265A, PO Box 42528, Philadelphia, PA 19101, USA. crandad@wyeth.com
Quinet
Elaine M
EM
El Ayachi
Soulaf
S
Hreha
Amy L
AL
Leik
Courtney E
CE
Savio
Dawn A
DA
Juhan-Vague
Irene
I
Alessi
Marie-Christine
MC
D000085:Acetates / Q000494:pharmacology*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development*; D000328:Adult; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007210:Indoleacetic Acids; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism
D000085:Acetates; D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin; D005947:Glucose