Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA.
Am J Physiol Endocrinol Metab. 2010 May;298(5):E1036-48. doi: 10.1152/ajpendo.00668.2009. Epub 2010 Feb 16.
Tissue macrophage inflammatory pathways contribute to obesity-associated insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (HE3286) in vitro and in vivo. In primary murine macrophages, HE3286 attenuates LPS- and TNFalpha-stimulated inflammation. In Zucker diabetic fatty rats, inflammatory cytokine/chemokine expression was downregulated in liver and adipose tissue by HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced inflammation, HE3286 treatment normalized fasting and fed glucose levels, improved glucose tolerance, and enhanced skeletal muscle and liver insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials, HE3286 treatment led to an enhancement in insulin sensitivity in humans. Gluconeogenic capacity was also reduced by HE3286 treatment, as evidenced by a reduced glycemic response during pyruvate tolerance tests and decreased basal hepatic glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that HE3286 treatment reduced liver cholesterol and triglyceride content, leading to a feedback elevation of LDL receptor and HMG-CoA reductase expression. Accordingly, HE3286 treatment markedly decreased total serum cholesterol. In conclusion, HE3286 is a novel anti-inflammatory compound, which displays both glucose-lowering and cholesterol-lowering effects.
组织巨噬细胞炎症途径有助于肥胖相关的胰岛素抵抗。在这里，我们研究了一种新型抗炎化合物（HE3286）在体外和体内的疗效和作用机制。在原代小鼠巨噬细胞中，HE3286 可减弱 LPS 和 TNFalpha 刺激的炎症。在 Zucker 糖尿病肥胖大鼠中，HE3286 治疗可下调肝脏和脂肪组织中炎症细胞因子/趋化因子的表达，并减少巨噬细胞浸润到脂肪组织中。与炎症减轻一致，HE3286 治疗使空腹和进食后血糖水平正常化，改善葡萄糖耐量，并通过高胰岛素正葡萄糖钳夹研究增强骨骼肌和肝脏胰岛素敏感性。在 2 期临床试验中，HE3286 治疗可增强人类的胰岛素敏感性。HE3286 治疗还降低了糖异生能力，这可通过丙酮酸耐量试验中的血糖反应降低和基础肝葡萄糖生成率（HGP）降低来证明。由于 HE3286 降低了糖异生底物的血清水平，这表明内在糖异生能力和底物可用性的降低共同导致 HGP 的降低。脂质组学分析显示，HE3286 治疗降低了肝脏胆固醇和甘油三酯含量，导致 LDL 受体和 HMG-CoA 还原酶表达的反馈升高。因此，HE3286 治疗显著降低了总血清胆固醇。总之，HE3286 是一种新型抗炎化合物，具有降低血糖和胆固醇的作用。
