SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice.
SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice.
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DOI：
10.1016/j.ebiom.2017.05.028
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发表时间：
2017-06
期刊：
影响因子：
11.1
通讯作者：
Ota T
中科院分区：
文献类型：
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作者：
Xu L;Nagata N;Nagashimada M;Zhuge F;Ni Y;Chen G;Mayoux E;Kaneko S;Ota T
钠-葡萄糖协同转运蛋白 (SGLT) 2 抑制剂可增加尿葡萄糖排泄 (UGE)，从而降低血糖和减轻体重。然而，SGLT2 抑制对能量稳态和肥胖引起的胰岛素抵抗的影响却鲜为人知。在这里，我们发现恩格列净（一种 SGLT2 抑制剂）可以增加高脂饮食诱导的肥胖 (DIO) 小鼠的能量消耗并减轻炎症和胰岛素抵抗。 C57BL/6J 小鼠采用高脂肪饮食 (HFD) 或 HFD 与恩格列净配对喂养 16 周。 Empagliflozin 给药增加了 DIO 小鼠的 UGE，而它抑制了 HFD 引起的体重增加、胰岛素抵抗和肝脂肪变性。此外，恩格列净将能量代谢转向脂肪利用，提高骨骼肌中 AMP 激活蛋白激酶和乙酰辅酶 A 羧化酶磷酸化，并提高肝脏和血浆成纤维细胞生长因子 21 水平。重要的是，恩格列净增加了棕色脂肪、腹股沟和附睾白色脂肪组织 (WAT) 中的能量消耗、产热以及解偶联蛋白 1 的表达。此外，恩格列净减少了 M1 极化巨噬细胞的积累，同时诱导 WAT 和肝脏内巨噬细胞的抗炎 M2 表型，降低血浆 TNFα 水平并减轻与肥胖相关的慢性炎症。因此，恩格列净通过增强脂肪利用和褐变来抑制体重增加，并通过极化 WAT 和肝脏中的 M2 巨噬细胞来减轻肥胖引起的炎症和胰岛素抵抗。恩格列净抑制 SGLT2 通过促进脂肪褐变来增强能量消耗和生热作用。 Empagliflozin 增强骨骼肌中的 AMPKα 和 ACC 磷酸化，并增加肝脏和血浆中 FGF21 的水平。 Empagliflozin 通过极化脂肪和肝脏中的 M2 巨噬细胞来减轻肥胖引起的炎症和胰岛素抵抗。恩格列净抑制钠-葡萄糖协同转运蛋白 2 (SGLT2) 可增加糖尿，从而降低高血糖和体重，对肥胖具有多效作用：(1) 恩格列净通过激活骨骼肌中的 AMPK 来促进脂肪利用。 (2)恩格列净增加血液中成纤维细胞生长因子(FGF)21的水平，促进脂肪组织褐变，从而增加产热和能量消耗。 (3) Empagliflozin 减少 M1 极化巨噬细胞积聚，同时诱导脂肪和肝脏内巨噬细胞的抗炎 M2 表型，减轻肥胖引起的炎症和胰岛素抵抗。
Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16 weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver. SGLT2 inhibition by empagliflozin enhances energy expenditure and thermogenesis by promoting the browning of fat. Empagliflozin enhances AMPKα and ACC phosphorylation in skeletal muscle and increases hepatic and plasma levels of FGF21. Empagliflozin attenuates obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in fat and liver. Sodium-glucose cotransporter 2 (SGLT2) inhibition by empagliflozin increases glucosuria, thereby reducing hyperglycaemia and weight with pleiotropic effects in obesity: (1) Empagliflozin promotes fat utilization by activating AMPK in skeletal muscle. (2) Empagliflozin increases fibroblast growth factor (FGF) 21 levels in blood and promotes browning of adipose tissue, thereby increasing thermogenesis and energy expenditure. (3) Empagliflozin reduces M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within fat and liver, attenuating obesity-induced inflammation and insulin resistance.