Hemin restores ACTH-induced glucocorticoid response in insulin-resistant rats

Abstract

A sustainedconsumption of sucrose rich diets has deleterious effects on the adrenal corteximpairing its steroidogenic capacity. As hemin treatment has been shown toexert cytoprotective effects (e.g. by heme oxygenase 1 induction), our maingoal was to analyze the adrenocortical function in rats treated with diet andhemin. Male Wistar rats fed standard chow and 30% sucrose in the drinking water(SRD) ad libitum for 12 weeks, were injected with hemin for the last 2 weeks oftreatment. mRNA and proteins were analyzed by RT-qPCR, western blot orimmunofluorescence, and corticosterone levels were assessed by RIA. A decreasein lipid peroxides and an increase in the activity of catalase were detected inthe SRD+H-group. Moreover, pro-inflammatory markers (TNFα, IL1β, CXCL10, MCP1, NALP3 and NOS2), IBA1+/ED1+ cells and NFκβ activation were still elevated in tissues fromSRD+H treated rats whereas an increase in markers of macrophages withM2-phenotype (ARG1, MRC1, TGFβ) was alsoshown. Activation of ER stress in SRD-treated rats (CHOP, XBP1s and P58IPK) andthe induction of apoptosis (TUNEL and BAX/BCL2 mRNA ratio) were also attenuatedby hemin. Finally, ACTH-stimulated glucocorticoid production, significantlydecrease in SRD-treated rats was upregulated by hemin. Consumption of SRDinvolves exposure of tissues to a higher metabolic load that could generateoxidative stress and a proinflammatory state. Deleterious consequences of theseprocesses could account for the significant decrease in the ACTH-induced corticosteroneoutput from the gland. By correcting these effects hemin treatment was able torestore the hormone induced adrenocortical response.