Air pollution-derived particulate matter dysregulates hepatic Krebs cycle, glucose and lipid metabolism in mice

Exposure to ambient air particulate matter (PM(2.5)) is well established as a risk factor for cardiovascular and pulmonary disease. Both epidemiologic and controlled exposure studies in humans and animals have demonstrated an association between air pollution exposure and metabolic disorders such as diabetes. Given the central role of the liver in peripheral glucose homeostasis, we exposed mice to filtered air or PM(2.5) for 16 weeks and examined its effect on hepatic metabolic pathways using stable isotope resolved metabolomics (SIRM) following a bolus of (13)C(6)-glucose. Livers were analyzed for the incorporation of (13)C into different metabolic pools by IC-FTMS or GC-MS. The relative abundance of (13)C-glycolytic intermediates was reduced, suggesting attenuated glycolysis, a feature found in diabetes. Decreased (13)C-Krebs cycle intermediates suggested that PM(2.5) exposure led to a reduction in the Krebs cycle capacity. In contrast to decreased glycolysis, we observed an increase in the oxidative branch of the pentose phosphate pathway and (13)C incorporations suggestive of enhanced capacity for the de novo synthesis of fatty acids. To our knowledge, this is one of the first studies to examine (13)C(6)-glucose utilization in the liver following PM(2.5) exposure, prior to the onset of insulin resistance (IR).