Sex-dependent effects of ambient PM_2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice

Background & aims: Emerging evidence supports ambient fine particulate matter (PM_2.5) exposure is associated with insulin resistance (IR) and hepatic lipid accumulation. In this study, we aimed to evaluate the sex-dependent vulnerability in response to PM_2.5 exposure and investigate the underlying mechanism by which PM_2.5 modulates hepatic lipid metabolism.

Methods: Both male and female C57BL/6 mice were randomly assigned to ambient PM_2.5 or filtered air for 24 weeks via a whole body exposure system. High-coverage quantitative lipidomics approaches and liquid chromatography-mass spectrometry techniques were performed to measure hepatic metabolites and hormones in plasma. Metabolic studies, histological analyses, as well as gene expression levels and molecular signal transduction analysis were applied to examine the effects and mechanisms by which PM_2.5 exposure-induced metabolic disorder.

Results: Female mice were more susceptible than their male counterparts to ambient PM_2.5 exposure-induced IR and hepatic lipid accumulation. The hepatic lipid profile was changed in response to ambient PM_2.5 exposure. Levels of hepatic triacylglycerols (TAGs), free fatty acids (FFAs) and cholesterol were only increased in female mice from PM group compared to control group. Plasmalogens were dysregulated in the liver from PM_2.5-exposed mice as well. In addition, exposure to PM_2.5 led to enhanced hepatic ApoB and microsomal triglyceride transport protein expression in female mice. Finally, PM_2.5 exposure inhibited hypothalamus-pituitary-adrenal (HPA) axis and decreased glucocorticoids levels, which may contribute to the vulnerability in PM_2.5-induced metabolic dysfunction.

Conclusions: Ambient PM_2.5 exposure inhibited HPA axis and demonstrated sex-associated differences in its effects on IR and disorder of hepatic lipid metabolism. These findings provide new mechanistic evidence of hormone regulation in air pollution-mediated metabolic abnormalities of lipids and more personalized care should be considered in terms of sex-specific risk factors.