Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet
Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet
复制标题
DOI：
10.1136/bmjdrc-2019-000783
复制
发表时间：
2019-10
影响因子：
4.1
通讯作者：
Liang Xu;N. Nagata;Guanliang Chen;M. Nagashimada;F. Zhuge;Y. Ni;Yuriko Sakai;S. Kaneko;Tsuguhito Ota
中科院分区：
文献类型：
--
作者：
Liang Xu;N. Nagata;Guanliang Chen;M. Nagashimada;F. Zhuge;Y. Ni;Yuriko Sakai;S. Kaneko;Tsuguhito Ota
目的研究钠-葡萄糖协同转运蛋白（SGLT）2的抑制剂恩格列净对肥胖的预防作用。然而，很难将这些结果外推到人类受试者身上。在此，我们进行了一项与人类临床情况更相关的治疗研究，以研究恩格列净的减肥作用，并阐明恩格列净介导的肥胖小鼠脂肪布朗宁增强的机制。研究设计和方法在高脂饮食（HFD）8周后，C57 BL/6 J小鼠表现出肥胖，伴有胰岛素抵抗和低度慢性炎症。肥胖小鼠队列继续接受HFD治疗额外8周，接受或不接受恩格列净治疗。结果恩格列净治疗8周可显著增加尿糖排泄，抑制HFD诱导的体重增加、胰岛素抵抗和肝脂肪变性。值得注意的是，恩格列净增加了氧气消耗和二氧化碳产生，导致能量消耗增加。因此，恩格列净给药小鼠棕色和白色（WAT）脂肪组织中解偶联蛋白1的表达水平均升高。此外，恩格列净降低了肥胖小鼠白细胞介素（IL）-6和单核细胞趋化蛋白-1的血浆水平，但增加了IL-33和脂联素的血浆水平。最后，我们发现恩格列净减少了M1极化的巨噬细胞蓄积，同时诱导了WAT和肝脏中巨噬细胞的抗炎M2表型，从而减轻了肥胖相关的慢性炎症。结论：恩格列净治疗通过增加能量消耗和脂肪组织布朗宁来减轻体重增加，并通过在肥胖小鼠的WAT和肝脏中交替激活巨噬细胞来减轻肥胖相关的炎症和胰岛素抵抗。
Objective We reported previously that empagliflozin—a sodium-glucose cotransporter (SGLT) 2 inhibitor—exhibited preventive effects against obesity. However, it was difficult to extrapolate these results to human subjects. Here, we performed a therapeutic study, which is more relevant to clinical situations in humans, to investigate antiobesity effects of empagliflozin and illustrate the mechanism underlying empagliflozin-mediated enhanced fat browning in obese mice. Research design and methods After 8 weeks on a high-fat diet (HFD), C57BL/6J mice exhibited obesity, accompanied by insulin resistance and low-grade chronic inflammation. Cohorts of obese mice were continued on the HFD for an additional 8-week treatment period with or without empagliflozin. Results Treatment with empagliflozin for 8 weeks markedly increased glucose excretion in urine, and suppressed HFD-induced weight gain, insulin resistance and hepatic steatosis. Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to increased energy expenditure. Consistently, the level of uncoupling protein 1 expression was increased in both brown and white (WAT) adipose tissues of empagliflozin-treated mice. Furthermore, empagliflozin decreased plasma levels of interleukin (IL)-6 and monocyte chemoattractant protein-1, but increased plasma levels of IL-33 and adiponectin in obese mice. Finally, we found that empagliflozin reduced M1-polarized macrophage accumulation, while inducing the anti-inflammatory M2 phenotype of macrophages in the WAT and liver, thereby attenuating obesity-related chronic inflammation. Conclusions Treatment with empagliflozin attenuated weight gain by increasing energy expenditure and adipose tissue browning, and alleviated obesity-associated inflammation and insulin resistance by alternative macrophage activation in the WAT and liver of obese mice.