Microglia Mediate Metabolic Dysfunction from Common Air Pollutants through NF-κB Signaling
Abstract
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 (Cx3cr1GFP∆IKK) or exclusively in microglia (Tmem119ER∆IKK) 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.
Article Highlights
· The first meta-analysis, establishing a robust association between exposure to benzene, a prevalent airborne VOC, and insulin resistance in humans across all ages.
· Short-term benzene exposure in male mice results in hyperglycemia and disruptions in energy balance.
· Acute benzene exposure triggers hypothalamic insulin resistance and provokes an inflammatory shift in the microglial transcriptome.
· The microglial NF-κB pathway is critical in mediating hyperglycemia and metabolic dysregulation induced by benzene exposure.
