PT - JOURNAL ARTICLE AU - Liang Xu AU - Naoto Nagata AU - Guanliang Chen AU - Mayumi Nagashimada AU - Fen Zhuge AU - Yinhua Ni AU - Yuriko Sakai AU - Shuichi Kaneko AU - Tsuguhito Ota TI - Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet AID - 10.1136/bmjdrc-2019-000783 DP - 2019 Oct 01 TA - BMJ Open Diabetes Research & Care PG - e000783 VI - 7 IP - 1 4099 - http://drc.bmj.com/content/7/1/e000783.short 4100 - http://drc.bmj.com/content/7/1/e000783.full SO - BMJ Open Diab Res Care2019 Oct 01; 7 AB - 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.