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

Title
A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice
Authors
Piao, LingjuanJung, InjiHuh, Joo YoungMiyata, ToshioHa, Hunjoo
Ewha Authors
하헌주
SCOPUS Author ID
하헌주scopus
Issue Date
2016
Journal Title
BRITISH JOURNAL OF PHARMACOLOGY
ISSN
0007-1188JCR Link1476-5381JCR Link
Citation
vol. 173, no. 17, pp. 2622 - 2632
Publisher
WILEY-BLACKWELL
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
BACKGROUND AND PURPOSE Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associatedmetabolic 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.
DOI
10.1111/bph.13541
Appears in Collections:
약학대학 > 약학과 > Journal papers
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