Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation

IF 27.7 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2025-02-19 DOI:10.1016/j.cmet.2025.01.006

Weijie Wu, Wenhai Sui, Sizhe Chen, Ziheng Guo, Xu Jing, Xiaolu Wang, Qun Wang, Xinshuang Yu, Wenjing Xiong, Jiansong Ji, Libo Yang, Yuan Zhang, Wenjing Jiang, Guohua Yu, Shuzhen Liu, Wei Tao, Chen Zhao, Yun Zhang, Yuguo Chen, Cheng Zhang, Yihai Cao

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Abstract

Consumption of artificial sweeteners (ASWs) in various foods and beverages has been linked to an increased risk of cardiovascular diseases (CVDs). However, molecular mechanisms underlying ASW-associated CVD remain unknown. Here, we show that consumption of 0.15% aspartame (APM) markedly increased insulin secretion in mice and monkeys. Bilateral subdiaphragmatic vagotomy (SDV) obliterated APM-elevated blood insulin levels, demonstrating crucial roles of parasympathetic activation in regulation of insulin secretion. Incessant APM feeding of ApoE^−/⁻ mice aggravated atherosclerotic plaque formation and growth via an insulin-dependent mechanism. Implantation of an insulin-slow-release pump in ApoE^−/− mice exacerbated atherosclerosis. Whole-genome expression profiling discovered that CX3CL1 chemokine was the most upregulated gene in the insulin-stimulated arterial endothelial cells. Specific deletion of a CX3CL1 receptor, Cx3cr1 gene, in monocytes/macrophages completely abrogated the APM-exacerbated atherosclerosis. Our findings uncover a novel mechanism of APM-associated atherosclerosis and therapeutic targeting of the endothelial CX3CL1-macrophage CX3CR1 signaling axis provides an approach for treating atherosclerotic CVD.

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甜味剂阿斯巴甜通过胰岛素引发的炎症加重动脉粥样硬化

食用各种食品和饮料中的人工甜味剂（ASWs）与心血管疾病（cvd）的风险增加有关。然而，asw相关CVD的分子机制尚不清楚。本研究表明，摄入0.15%阿斯巴甜（APM）可显著增加小鼠和猴子的胰岛素分泌。双侧膈下迷走神经切开术（SDV）消除了apm升高的血胰岛素水平，表明副交感神经激活在调节胰岛素分泌中的重要作用。不间断的APM喂养ApoE - / -小鼠通过胰岛素依赖机制加剧了动脉粥样硬化斑块的形成和生长。在ApoE−/−小鼠中植入胰岛素缓释泵会加重动脉粥样硬化。全基因组表达谱分析发现，CX3CL1趋化因子在胰岛素刺激的动脉内皮细胞中表达上调最多。单核细胞/巨噬细胞特异性缺失CX3CL1受体Cx3cr1基因，可完全消除apm加重的动脉粥样硬化。我们的研究结果揭示了apm相关动脉粥样硬化的新机制，内皮细胞cx3cl1 -巨噬细胞CX3CR1信号轴的治疗靶向为治疗动脉粥样硬化性CVD提供了一种方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.