1. A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice.
- Author
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Piao, Lingjuan, Jung, Inji, Huh, Joo Young, Miyata, Toshio, and Ha, Hunjoo
- Subjects
PLASMINOGEN activator inhibitors ,HIGH-fat diet ,OBESITY ,FAT cells ,CHRONIC diseases ,METABOLIC disorders ,LABORATORY mice ,PREVENTION of obesity ,PROTEIN metabolism ,ANIMAL experimentation ,ANIMALS ,ARGININE ,BIOCHEMISTRY ,DIET ,DOSE-effect relationship in pharmacology ,HETEROCYCLIC compounds ,PHENOMENOLOGY ,MICE ,PROTEINS ,CARBOCYCLIC acids ,CHEMICAL inhibitors - Abstract
Background and Purpose: Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associated metabolic disorder. The level of plasma plasminogen activator inhibitor-1 (PAI-1) is increased in obese subjects, and PAI-1 null mice show 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. 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.Experimental Approach: Ten-week-old C57BL/6J mice were fed 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(-1) oral gavage) was administered daily with the initiation of HFD.Key Results: TM5441 prevented HFD-induced body weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulated JNK and Akt phosphorylation, suggesting that it prevents the insulin resistance of adipocytes. TM5441 also attenuated the macrophage infiltration and increased expression of 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 prevent adipocyte inflammation and dysregulation by maintaining mitochondrial fitness.Conclusion and Implications: Our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders. [ABSTRACT FROM AUTHOR]- Published
- 2016
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