Novel Plasminogen Activator Inhibitor-1 Inhibitor Protects Against High Fat Diet-induced Obesity and Adipocyte Injury in Mice > Newsletter

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Novel Plasminogen Activator Inhibitor-1 Inhibitor Protects Against High Fat Diet-induced Obesity and Adipocyte Injury in Mice 

 

 

 

 

by Prof. Hunjoo Ha (hha@ewha.ac.kr)

Department of Pharmaceutical Sciences, College of Pharmacy

 

 


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Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associated metabolic disorder. It is, thus, important to find a novel molecular mechanism of obesity in order to provide an effective treatment. Classical view of plasminogen activator inhibitor (PAI-1) is an endogenous inhibitor of t-PA and plasmin system, thus promoting thrombosis. However, the recent data suggest that PAI-1 is a novel molecule involved in aging-associated diseases including obesity, insulin resistance, diabetes, and diabetic complications.

​In fact, the level of PAI-1 is increased in obese subjects, and PAI-1 null mice showed improved insulin sensitivity when subjected to high-fat and high-sucrose diet-induced metabolic stress, suggesting that a best-in-class PAI-1 inhibitor may become a novel therapeutic agent for obesity-associated metabolic syndrome. Having been developed by our collaborator, Professor Toshio Miyata at Tohoku University, Japan, TM5441 is a novel orally active PAI-1 inhibitor that does not cause bleeding episodes. Hence, in the present study we examined the preventive effect of TM5441 on high-fat diet (HFD)-induced adipocyte dysfunction.

Ten-week-old C57BL/6J mice were fed with a normal diet (18% of total calories from fat) or HFD (60% of total calories from fat) for 10 weeks, and TM5441 (20 mg/kg, oral gavage) was administered daily, along with the initiation of HFD.

​TM5441 prevented HFD-induced body weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulated JNK and Akt phosphorylation, suggesting that it prevents insulin resistance in adipocytes. TM5441 also attenuated macrophage infiltration and reduced the highly-expressed pro-inflammatory cytokines, such as inducible nitric oxide synthase, induced by the HFD. In addition, TM5441 prevented the HFD-induced down-regulation of genes involved in mitochondrial biogenesis and function, suggesting that it may also prevent adipocyte inflammation and dysregulation by maintaining mitochondrial fitness.

​In another study, we also found that delayed treatment with TM 5441 protects against HFD-induced obesity and adipocyte injury in mice. Overall, our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders.

​TM5441 has now been developed to a clinical candidate with improved efficacy and decreased toxicity through further structural optimization. A clinical candidate is currently under investigator-driven clinical trials.

 

​B. PAI-1                                                 A. TM5441 prevents obesity, adipocyte hypertrophy,

                                                                   macrophage infiltration

 

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* Related Article

Piao L, Jung I, Huh JY, Miyata T, Ha H: A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high fat diet-induced obesity and adipocyte injury in mice. Br J Pharmacol 173:2622-2632, 2016

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