Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice.
Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice.
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DOI：
10.1371/journal.pone.0150756
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Katagiri H
中科院分区：
文献类型：
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作者：
Chiba Y;Yamada T;Tsukita S;Takahashi K;Munakata Y;Shirai Y;Kodama S;Asai Y;Sugisawa T;Uno K;Sawada S;Imai J;Nakamura K;Katagiri H
选择性葡萄糖共转运蛋白-2抑制剂钠（SGLT2i）治疗促进尿糖排泄，从而降低血糖和体重。然而，SGLT2i治疗只能实现有限的体重减轻。据报道，嗜食是导致体重减轻有限的原因之一。然而，SGLT2i治疗对全身能量消耗的影响尚未完全阐明。在这里，我们研究了达格列净（一种SGLT2i）对小鼠全身能量消耗的急性影响。达格列净处理18小时后，与车辆处理相比，耗氧量和生热相关基因ucp1的棕色脂肪组织（BAT）表达显著降低。此外，达格列净显著抑制BAT中去甲肾上腺素（NE）的转换和吻侧raphe pallidus核（rRPa）中c-fos的表达，吻侧raphe pallidus核包含负责产热的交感前运动神经元。这些发现表明，达格列净介导的能量消耗的急性减少涉及通过rRPa的交感神经活动减少BAT产热的减少。此外，肝总支迷走神经切断术消除了BAT中ucp1表达和NE含量以及rRPa中c-fos表达的减少。此外，肝碳水化合物代谢的改变，如糖原含量的降低和磷酸烯醇丙酮酸羧激酶的上调，在BAT产热抑制之前就表现出来，例如在达格列净治疗后6小时。总之，这些结果表明，SGLT2i治疗通过调节由肝总迷走神经和交感神经组成的器官间神经网络，急性抑制BAT的能量消耗。
Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves.