Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry
Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry
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DOI：
10.1016/j.bbrc.2017.09.081
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发表时间：
2017-11-04
影响因子：
3.1
通讯作者：
Yahagi, Naoya
中科院分区：
文献类型：
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作者：
Sawada, Yoshikazu;Izumida, Yoshihiko;Yahagi, Naoya
钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂具有抗糖尿病和抗肥胖作用。然而，抗肥胖作用的确切机制仍不清楚。我们先前证明了糖原消耗信号通过肝-脑-脂肪神经回路触发脂肪组织中的脂解。因此，在本研究中，我们研究了SGLT 2抑制剂的抗肥胖机制是否由该机制介导。对饮食诱导的肥胖小鼠进行肝迷走神经切断术（HVx）或假手术，并给予含0.015%托福格列汀（TOFU）（一种高选择性SGLT 2抑制剂）的高脂肪饲料3周。TOFU处理的小鼠显示脂肪量减少，并且在HVx组中TOFU的作用减弱。尽管HVx和假手术小鼠通过TOFU处理显示出相似的肝糖原减少水平，但与假手术组相比，HVx小鼠在白色脂肪组织中通过蛋白激酶A（PICA）表现出减弱的蛋白磷酸化反应。由于已知PKA途径作为肝-脑-脂肪轴的效应物并激活脂肪细胞中的甘油三酯脂肪酶，因此这些结果表明SGLT 2抑制触发糖原耗竭信号并激活肝-脑-脂肪轴，导致脂肪细胞中的PICA激活。综上所述，可以得出结论，SGLT 2抑制对体重减轻的影响部分通过肝-脑-脂肪神经回路介导。(C)2017爱思唯尔公司All rights reserved.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFU), a highly selective SGLT2 inhibitor, for 3 weeks. TOFU-treated mice showed a decrease in fat mass and the effect of TOFU was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFU treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PICA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PICA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry. (C) 2017 Elsevier Inc. All rights reserved.