Novel Plasminogen Activator Inhibitor-1 Inhibitor Protects Against High Fat Diet-induced Obesity and Adipocyte Injury in Mice
by Prof. Hunjoo Ha (firstname.lastname@example.org)
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,
* 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