The prevalence of Type 2 Diabetes (T2D) poses a significant health challenge yet the contribution of air pollutants to T2D epidemics remains understudied. 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 utilized a controlled benzene exposure system, continuous glucose monitoring (CGM) 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 reveals 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, 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.

中文翻译：

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小胶质细胞通过 NF-κB 信号传导介导常见空气污染物的代谢功能障碍


2 型糖尿病 （T2D） 的患病率构成了重大的健康挑战，但空气污染物对 T2D 流行病的影响仍未得到充分研究。几项研究表明，室内/室外环境中暴露于挥发性有机化合物 （VOC） 与 T2D 之间存在相关性。在这里，我们进行了第一次荟萃分析，确定了苯（一种普遍的空气传播 VOC）暴露与所有年龄段人类的胰岛素抵抗之间的强大关联。我们在小鼠中使用受控苯暴露系统、连续血糖监测 （CGM） 方法和间接量热法来研究潜在机制。暴露后，仅在男性中观察到能量稳态的破坏，伴随着下丘脑转录组的改变以及胰岛素和免疫信号的改变，导致血糖水平飙升。一致，小胶质细胞的 RNA 测序显示与免疫反应和 NF-κB 信号传导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） 中选择性消融 IKKβ 可缓解苯诱导的神经胶质增生，恢复能量稳态、下丘脑基因表达，并防止高血糖。我们得出结论，小胶质细胞 NF-κB 通路在化学诱导的代谢紊乱中起关键作用，揭示了将暴露于空气传播的毒物与代谢疾病的发作联系起来的重要病理生理机制。