Journal
OBESITY
Volume 29, Issue 4, Pages 713-720Publisher
WILEY
DOI: 10.1002/oby.23112
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Funding
- National Institutes of Health [1K08DK095992]
- VA Merit Award [BX003854-01]
- Endocrine Fellows Foundation
- Irving S. Cutter Endowment
- Ruth L. Kirschstein National Research Service Award from the NIDDK [T32 DK007169]
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Pharmacologic PAI-1 inhibition with TM5441 stimulates adipose tissue lipolysis and enhances weight loss in obese mice. The combination of TM5441 with dietary modification leads to greater weight loss and faster reversal of hepatic steatosis in obese mice compared to dietary modification alone. Increased expression of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and phosphorylated perilipin-1 in adipose tissue was associated with enhanced weight loss in mice treated with TM5441.
Objective This study investigates the therapeutic potential of a small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1), TM5441, in reversing diet-induced obesity in mice. Methods Wild-type C57BL/6J mice were fed a high-fat high-sugar (HFHS) diet for 8 weeks to induce obesity. After the first 8 weeks, TM5441 was added to the diet for an additional 8 weeks. In order to determine the efficacy of PAI-1 inhibition in conjunction with dietary modification, mice were fed an HFHS diet for 8 weeks to induce obesity and were then switched to a low-fat diet with or without TM5441 for an additional 2 to 8 weeks. Results Obese mice showed weight reduction and significant improvement in hepatic steatosis when TM5441 was added to the HFHS diet. Obese mice that were treated with TM5441 in conjunction with dietary modification showed enhanced weight loss and a more rapid reversal of hepatic steatosis compared with obese mice treated with dietary modification alone. The enhanced weight loss among mice treated with TM5441 was associated with increased adipose tissue expression of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and phosphorylated perilipin-1 as well as induction of adipose tissue lipolysis. Conclusions Pharmacologic PAI-1 inhibition stimulates adipose tissue lipolysis and enhances weight loss in obese mice.
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