There is growing evidence linking exposure to volatile organic compounds (VOC) in ambient air with metabolic disease in humans. Benzene is a prominent VOC present in water, food, detergents, vehicle exhaust, tobacco smoke, and e-cigarettes. However, a direct link between exposure to VOC and metabolic homeostasis is not yet established. We performed a meta-analysis and found a positive association between exposure to VOC and metabolic impairments. Using a highly controlled mouse exposure system, we have recently demonstrated that chronic exposure of mice to VOC induces neuroinflammation and insulin resistance predisposing to T2D. To establish a timeline for the onset of VOC-triggered metabolic effects, we monitored glucose changes of exposed mice using continuous glucose monitoring (CGM) system. Surprisingly, we detected significant changes in glycemic control of male mice starting at day 4 of exposure. Further, mice exhibited impaired parameters of energy homeostasis within 6h of exposure. This was associated with activation of hypothalamic gliosis via stimulation of the NF-κB signaling and dysregulation of hypothalamic insulin signaling, contributing to blunted responses to glucose stimulation in glucose-sensing neurons. To determine the role of the central inflammatory mechanism in VOC-induced metabolic imbalance, we genetically ablated NF-κB signaling in microglia using Cx3cr1creERΔIKK mice. Selective inhibition of microglial NF-κB signaling completely restored hypothalamic insulin signaling, astrocytes activation, and hypothalamic glucose-sensing, consequently protecting from whole-body metabolic imbalance induced by VOC exposure. Importantly, this effect was mediated via hypothalamic ER stress response. Collectively, our data provide evidence that neuroinflammatory responses precede and mechanistically contribute to whole-body metabolic imbalance and identify air pollution-induced cellular and molecular targets in the hypothalamus that lead to metabolic disease.
L.K.Debarba: n/a. L.Koshko: None. H.M.Jayarathne: None. Z.Yi: None. U.Klueh: Research Support; Dexcom, Inc. M.Sadagurski: None.
American Diabetes Association (1-18-JDF-063)