Piao Lingjuan, Jung Inji, Huh Joo Young, Miyata Toshio, Ha Hunjoo
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
Colleges of Pharmacy, Chonnam National University, Gwang-Ju, Korea.
Br J Pharmacol. 2016 Sep;173(17):2622-32. doi: 10.1111/bph.13541. Epub 2016 Jul 28.
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.
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.
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.
Our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders.
肥胖是全球最普遍的慢性疾病之一，脂肪细胞功能失调在肥胖相关的代谢紊乱中起重要作用。肥胖受试者血浆纤溶酶原激活物抑制剂-1（PAI-1）水平升高，且PAI-1基因敲除小鼠在高脂高糖饮食诱导的代谢应激下胰岛素敏感性得到改善，这表明一种一流的PAI-1抑制剂可能成为治疗肥胖相关代谢综合征的新型药物。TM5441是一种新型口服活性PAI-1抑制剂，不会引起出血事件。因此，在本研究中，我们检测了TM5441对高脂饮食（HFD）诱导的脂肪细胞功能障碍的预防作用。
将10周龄的C57BL/6J小鼠喂食正常饮食（脂肪提供总热量的18%）或HFD（脂肪提供总热量的60%）10周，并在开始给予HFD时每天口服灌胃TM5441（20 mg·kg⁻¹）。
TM5441可预防HFD诱导的体重增加和全身胰岛素抵抗。TM5441使HFD诱导的JNK和Akt磷酸化失调恢复正常，表明它可预防脂肪细胞的胰岛素抵抗。TM5441还减弱了巨噬细胞浸润，并降低了HFD诱导的促炎细胞因子（如诱导型一氧化氮合酶）的表达增加。此外，TM5441可预防HFD诱导的参与线粒体生物发生和功能的基因下调，表明它可能通过维持线粒体健康来预防脂肪细胞炎症和失调。
我们的数据表明，TM5441可能成为治疗肥胖及肥胖相关代谢紊乱的新型药物。
