Debarba Lucas K, Jayarathne Hashan S M, Stilgenbauer Lukas, Dos Santos Ana L Terra, Koshko Lisa, Scofield Sydney, Sullivan Ryan, Mandal Abhijit, Klueh Ulrike, Sadagurski Marianna
Department of Biological Sciences, Wayne State University, Detroit, MI.
Department of Mathematical Sciences, University of Texas at El Paso, El Paso, TX.
Diabetes. 2024 Dec 1;73(12):2065-2077. doi: 10.2337/db24-0110.
The prevalence of type 2 diabetes (T2D) poses a significant health challenge, yet the contribution of air pollutants to T2D epidemics remains under-studied. Several studies demonstrated a correlation between exposure to volatile organic compounds (VOCs) in indoor/outdoor environments and T2D. Here, we conducted the first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages. We used a controlled benzene exposure system, continuous glucose monitoring approach, and indirect calorimetry in mice, to investigate the underlying mechanisms. Following exposure, disruptions in energy homeostasis, accompanied by modifications in the hypothalamic transcriptome and alterations in insulin and immune signaling, were observed exclusively in males, leading to a surge in blood glucose levels. In agreement, RNA sequencing of microglia revealed increased expression of genes associated with immune response and NF-κB signaling. Selective ablation of IKKβ in immune cells (Cx3cr1GFPΔIKK) or exclusively in microglia (Tmem119ERΔIKK) in adult mice alleviated benzene-induced gliosis, restored energy homeostasis and hypothalamic gene expression, and protected against hyperglycemia. We conclude that the microglial NF-κB pathway plays a critical role in chemical-induced metabolic disturbances, revealing a vital pathophysiological mechanism linking exposure to airborne toxicants and the onset of metabolic diseases.
2型糖尿病（T2D）的流行对健康构成了重大挑战，然而空气污染物对T2D流行的影响仍未得到充分研究。多项研究表明，室内/室外环境中挥发性有机化合物（VOCs）的暴露与T2D之间存在关联。在此，我们进行了首次荟萃分析，确立了普遍存在的空气传播VOC苯的暴露与各年龄段人群胰岛素抵抗之间的强有力关联。我们使用了苯暴露控制系统、连续血糖监测方法以及小鼠间接量热法来研究潜在机制。暴露后，仅在雄性小鼠中观察到能量稳态的破坏，同时伴有下丘脑转录组的改变以及胰岛素和免疫信号的变化，导致血糖水平飙升。与此一致的是，小胶质细胞的RNA测序显示与免疫反应和NF-κB信号相关的基因表达增加。在成年小鼠的免疫细胞（Cx3cr1GFPΔIKK）或仅在小胶质细胞（Tmem119ERΔIKK）中选择性敲除IKKβ可减轻苯诱导的胶质增生，恢复能量稳态和下丘脑基因表达，并预防高血糖。我们得出结论，小胶质细胞NF-κB途径在化学物质诱导的代谢紊乱中起关键作用，揭示了一种将空气传播毒物暴露与代谢疾病发作联系起来的重要病理生理机制。
