title: Modulation of adipose tissue development by pharmacological inhibition of PAI-1.
abstract: 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.
authors.affiliation: Cardiovascular and Metabolic Disease Research, Wyeth Research, N2265A, PO Box 42528, Philadelphia, PA 19101, USA. crandad@wyeth.com
authors.forename: David L
authors.initials: DL
authors.lastname: Crandall
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Quinet
authors.forename: Soulaf
authors.initials: S
authors.lastname: El Ayachi
authors.forename: Amy L
authors.initials: AL
authors.lastname: Hreha
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Leik
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Savio
authors.forename: Irene
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
mesh_terms: 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
chemical_list: D000085:Acetates; D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin; D005947:Glucose