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

다국어 초록 (Multilingual 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 subjucts, 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 (20mgㆍkg^-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 dysregu-lated 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.
Abbreviations
ATGL, adipose triglyceride lipase; Cox, cytochrome c oxidase; FAS, fatty acid synthase; FFA, free fatty acid; GTT, glucose tolerance test; H&E, haematoxylin and eosin; HFD, high-fat diet; HSL, hormone-sensitive lipase; iNOS, inducible nitric oxide synthase; ITT, insulin tolerance test; KO, knockout; MCP-1, monocyte chemotactic protein-1; mtDNA, mitochon-drial DNA; ND, normal diet; PAI-1, plasminogen activator inhibitor-1; PGC1α, PPARγ coactivator-1α; Tfam, mitochondrial transcription factor A; TG, triglyceride; TM5275, 5-chloro-2-[({2-[4-(diphenylmethyl)piperazin-1-yl]-2-oxoethoxy}acetyl) amino]benzoate; TM5441, 5-chloro-2{[(2-{[3-(furan-3-yl)phenyl]amino}-2-oxoethoxy) acethyl]amino} benzoic acid; UCP, uncoupling protein; WAT, white adipose tissue