Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. Issue 1 (25th October 2019)

• Record Type: Journal Article
• Authors: Xu, Liang; Nagata, Naoto; Chen, Guanliang; Nagashimada, Mayumi; Zhuge, Fen; Ni, Yinhua; Sakai, Yuriko; Kaneko, Shuichi; Ota, Tsuguhito
• Is Part Of: BMJ open diabetes research and care. Volume 7:Issue 1(2019)
• Publication Date: 2019-10-25
• Subjects: Obesity -- Brown Fat -- Energy Expenditure -- Sodium Glucose Cotransporter; Diabetes -- Periodicals; 616.462005
• DOI: 10.1136/bmjdrc-2019-000783
• Languages: English
• ISSNs: 2052-4897

Abstract

Abstract : 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.