Glucocorticoid and beta-adrenergic receptor antagonists inhibit ozone-induced metabolic response
On this page:
Inhalation of air pollutants has been linked to neuroendocrine stress-induced systemic metabolic and innate immune effects through increased circulating adrenaline and glucocorticoids. We have shown that ozone-induced pulmonary injury and inflammation are mediated through the activation of beta-adrenergic receptors (BAR) and glucocorticoid receptors (GR). Since air pollution has been linked to increased incidence of diabetes and obesity, assessing the contribution of stress mediators in metabolic homeostasis can aid in understanding the mechanisms. The purpose of this study was to examine if BAR and GR are involved in ozone-induced systemic and liver metabolic alterations. To determine the impact of BAR and GR individually or in combination, we treated 11-13-week-old male Wistar-Kyoto rats with propranolol (PROP), a non-specific BAR antagonist, and mifepristone (MIFE), a GR antagonist. Treatments began 7 days prior to air or ozone (0.8 ppm x 4 h) exposure and ended the day of exposure. Animals received injections of 1) saline or PROP (10 mg/kg/day, i.p.); 2) corn oil or MIFE (30 mg/kg/day, s.c.) or 3) both PROP+MIFE. As reported previously, ozone induced hyperglycemia and glucose intolerance. Ozone-induced hyperglycemia was mitigated by MIFE and PROP+MIFE but not PROP alone, however, both drugs reduced ozone-induced glucose intolerance. Circulating cholesterol (CHOL) and free fatty acids (FFA) increased after ozone exposure as we have observed in other studies. This effect on CHOL was mitigated by MIFE and PROP+MIFE, but not PROP. Ozone effect on FFA was mitigated by MIFE and/or PROP. Liver expression of genes involved in glucose and lipid metabolic processes showed ozone-induced increases in glucose 6-phosphatase (G6pc) and hexokinase-2. The effect on G6pc was mitigated by MIFE suggesting a role of GR in ozone-increased gluconeogenesis. Ozone increased expression of carnitine palmitoyl transferase 2, peroxisome proliferator activated receptor alpha and gamma, and decreased steroid responsive element binding factor 2, however, neither PROP nor MIFE had any influence on these trends. In conclusion, while GR activation played a major role in ozone-induced glucose and lipid metabolic changes, BAR inactivation was associated with mitigation of peripheral glucose uptake. Thus, ozone-induced homeostatic metabolic changes support epidemiological observations, and could contribute to metabolic syndrome in susceptible individuals. (This abstract does not reflect the US EPA policy).