Microglial NF-KB Signaling Deficiency Protects Against Metabolic Disruptions Caused by Volatile Organic Compound via Modulating the Hypothalamic Transcriptome
Prolonged exposure to benzene, a prevalent volatile organic compound (VOC) at concentrations found in smoke, triggers hyperglycemia, hyperinsulinemia, and inflammation in both the periphery and the hypothalamus of mice. Corroborating this with existing epidemiological data, we note a strong correlation between environmental exposure to benzene and metabolic impairments in humans. The goal of the current study was to elucidate the underlying mechanisms of this metabolic disruption. Utilizing a controlled exposure system coupled with continuous glucose monitoring (CGM), we report a rapid increase in blood glucose levels and disruptions in energy homeostasis post-benzene exposure in WT mice. This phenomenon was attributed to modifications in the hypothalamic transcriptome, specifically affecting genes involved in insulin and immune response pathways. As a result, mice exposed to benzene exhibited diminished insulin sensitivity and increased gliosis in the hypothalamus. Interestingly, short-term exposure to benzene induced microglia transcriptional activation that was characterized by increased expression of genes linked to immune response and the modulation of NF-KB transcription factor activity. Remarkably, the selective removal of IKKB in immune cells or exclusively in adult microglia in mice mitigated benzene-induced hypothalamic gliosis, and protected against hyperglycemia. In summary, our study uncovers a crucial pathophysiological mechanism, forging a clear connection between airborne toxicant exposure and the onset of metabolic diseases.