Modulation of insulin signaling pathway genes by ozone inhalation and the role of glucocorticoids: A multi-tissue analysis

Air pollution is associated with increased risk of metabolic diseases including type 2 diabetes, of which dysre-gulation of the insulin-signaling pathway is a feature. While studies suggest pollutant exposure alters insulin signaling in certain tissues, there is a lack of comparison across multiple tissues needed for a holistic assessment of metabolic effects, and underlying mechanisms remain unclear. Air pollution increases plasma levels of glu-cocorticoids, systemic regulators of metabolic function. The objectives of this study were to 1) determine effects of ozone on insulin-signaling genes in major metabolic tissues, and 2) elucidate the role of glucocorticoids. Male Fischer-344 rats were treated with metyrapone, a glucocorticoid synthesis inhibitor, and exposed to 0.8 ppm ozone or clean air for 4 h, with tissue collected immediately or 24 h post exposure. Ozone inhalation resulted in distinct mRNA profiles in the liver, brown adipose, white adipose and skeletal muscle tissues, including effects on insulin-signaling cascade genes (Pik3r1, Irs1, Irs2) and targets involved in glucose metabolism (Hk2, Pgk1, Slc2a1), cell survival (Bcl2l1), and genes associated with diabetes and obesity (Serpine1, Retn, Lep). Glucocorticoid-dependent regulation was observed in the liver and brown and white adipose tissues, while ef-fects in skeletal muscle were largely unaffected by metyrapone treatment. Gene expression changes were accompanied by altered phosphorylation states of insulin-signaling proteins (BAD, GSK, IR-beta, IRS-1) in the liver. The results show that systemic effects of ozone inhalation include tissue-specific regulation of insulin-signaling pathway genes via both glucocorticoid-dependent and independent mechanisms, providing insight into mech-anisms underlying adverse effects of pollutants.

Automated summary

Air pollution is associated with increased risk of metabolic diseases such as type 2 diabetes due to the dysregulation of the insulin-signaling pathway. This study aimed to investigate the effects of ozone on insulin-signaling genes in major metabolic tissues and explore the role of glucocorticoids. Results showed that ozone inhalation led to distinct mRNA profiles and altered phosphorylation states of insulin-signaling proteins, indicating tissue-specific regulation of insulin-signaling pathway genes through glucocorticoid-dependent and independent mechanisms.