Article Impact Level: HIGH Data Quality: STRONG Summary of Cell Metabolism, S1550413125000063. https://doi.org/10.1016/j.cmet.2025.01.006 Dr. Weijie Wu et al.
Points
- Consumption of aspartame (APM) increased insulin secretion in mice and monkeys through parasympathetic activation, as evidenced by the elimination of this effect after subdiaphragmatic vagotomy.
- Chronic APM consumption worsened atherosclerosis in ApoE−/− mice, with an insulin-dependent mechanism driving plaque formation, further confirmed by worsened lesions after insulin pump implantation.
- Whole-genome profiling identified CX3CL1 as the most upregulated gene in insulin-stimulated arterial endothelial cells, linking insulin signaling to endothelial inflammation.
- Deletion of the CX3CL1 receptor (Cx3cr1) in monocytes/macrophages prevented APM-induced atherosclerosis, highlighting the pathway’s role in disease progression.
- The study suggests that targeting the CX3CL1-CX3CR1 signaling axis could be a potential therapeutic strategy for managing atherosclerotic cardiovascular disease associated with artificial sweetener consumption.
Summary
This study investigates the molecular mechanisms by which aspartame (APM), an artificial sweetener, contributes to cardiovascular diseases (CVD), specifically atherosclerosis. The researchers found that consumption of 0.15% APM increased insulin secretion in mice and monkeys. This effect was mediated through parasympathetic activation, as bilateral subdiaphragmatic vagotomy (SDV) eliminated the APM-induced increase in insulin levels, indicating the crucial role of parasympathetic pathways in regulating insulin secretion. The study further demonstrated that chronic APM consumption exacerbated atherosclerosis in ApoE−/− mice, an insulin-dependent mechanism contributing to plaque formation and growth. Additionally, the implantation of an insulin-slow-release pump in these mice also worsened atherosclerotic lesions, underscoring the role of insulin in this process.
Whole-genome expression profiling revealed that the CX3CL1 chemokine was the most upregulated gene in insulin-stimulated arterial endothelial cells. The study then showed that specific deletion of the CX3CL1 receptor (Cx3cr1) in monocytes/macrophages effectively prevented the APM-induced exacerbation of atherosclerosis. This finding highlights the CX3CL1-CX3CR1 signaling pathway as a critical mediator in the insulin-induced endothelial inflammation that promotes atherosclerosis. The study suggests that targeting this signaling axis could provide a therapeutic approach for treating atherosclerotic cardiovascular diseases (CVD) aggravated by aspartame consumption.
In conclusion, the study elucidates a novel mechanism by which APM exacerbates atherosclerosis through insulin-dependent pathways and endothelial inflammation mediated by CX3CL1 and CX3CR1. These findings suggest that manipulating the CX3CL1-CX3CR1 signaling axis may offer potential therapeutic strategies for treating atherosclerotic CVD, especially in individuals with excessive artificial sweetener consumption.
Link to the article: https://www.sciencedirect.com/science/article/pii/S1550413125000063
References Wu, W., Sui, W., Chen, S., Guo, Z., Jing, X., Wang, X., Wang, Q., Yu, X., Xiong, W., Ji, J., Yang, L., Zhang, Y., Jiang, W., Yu, G., Liu, S., Tao, W., Zhao, C., Zhang, Y., Chen, Y., … Cao, Y. (2025). Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. Cell Metabolism, S1550413125000063. https://doi.org/10.1016/j.cmet.2025.01.006
