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A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice.

Authors :
Piao, Lingjuan
Jung, Inji
Huh, Joo Young
Miyata, Toshio
Ha, Hunjoo
Source :
British Journal of Pharmacology. Sep2016, Vol. 173 Issue 17, p2622-2632. 11p. 2 Charts, 5 Graphs.
Publication Year :
2016

Abstract

<bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusion and Implications: </bold>Our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00071188
Volume :
173
Issue :
17
Database :
Academic Search Index
Journal :
British Journal of Pharmacology
Publication Type :
Academic Journal
Accession number :
117297237
Full Text :
https://doi.org/10.1111/bph.13541