Modulation of Adipose Tissue Development by Pharmacological Inhibition of PAI-1

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 10; pp. 2209 - 2215
• Main Authors: Crandall, David L, Quinet, Elaine M, El Ayachi, Soulaf, Hreha, Amy L, Leik, Courtney E, Savio, Dawn A, Juhan-Vague, Irene, Alessi, Marie-Christine
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-10-2006; Hagerstown, MD Lippincott
• Subjects: Acetates - pharmacology; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Adipose Tissue - anatomy & histology; Adipose Tissue - drug effects; Adipose Tissue - growth & development; Adult; Animals; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Body Weight - drug effects; Cardiology. Vascular system; Cell Count; Cell Differentiation - drug effects; Cells, Cultured; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Glucose - pharmacology; Humans; Indoleacetic Acids; Indoles - pharmacology; Medical sciences; Mice; Mice, Inbred C57BL; Organ Size - drug effects; Orthopedic surgery; Plasminogen Activator Inhibitor 1 - blood; Plasminogen Activator Inhibitor 1 - metabolism; Stem Cells - drug effects; Stem Cells - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Endocrinopathy; Vascular disease; Adipocyte; Obesity; Adipose tissue; Diabetes mellitus; Nutrition disorder; Atherosclerosis; Cardiovascular disease; PAI-1; diabetes; Nutritional status
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000235605.51400.9d

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.