Alterations in glucocorticoid homeostasis following sleeve gastrectomy in male mice

Elevated intratissue levels of active glucocorticoids in patients with obesity are associated with insulin resistance, diabetes, impaired immune regulation, and other adverse effects. Sleeve gastrectomy (SG) induces significant weight loss and improves metabolic outcomes, including insulin resistance and hyperlipidemia. Among the enzymes controlling intracellular concentrations of active glucocorticoids, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1 and SDR26C1) has been extensively studied concerning obesity and postgastric surgery interventions. However, most studies focused on either a single tissue, circulating glucocorticoid levels, or HSD11B1 activity. In this work, we showed that the circulating active/inactive glucocorticoid ratio [corticosterone (B)/11-dehydrocorticosterone (A)] negatively correlated with glucose tolerance. In male C57BL/6 mice, SG slightly reduced circulating mineralocorticoids and reversed the elevated B/A ratio seen in sham-operated mice after a high-fat diet, while improving glucose tolerance. This change was likely due to increased renal 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2 and SDR9C3) activity after SG. To provide a comprehensive overview of the systemic effects postsurgery, we evaluated enzymes involved in glucocorticoid homeostasis across tissues on mRNA, protein, and activity levels. Moreover, mRNA expression levels of transcription factors CCAAT enhancer-binding protein alpha and beta and nuclear factor kappa b, as well as cytokines influencing Hsd11b1 and Hsd11b2 gene expression, were analyzed. The results emphasize the stronger influence of renal HSD11B2 than hepatic HSD11B1 activity on the circulating B/A ratio, supported by intrarenal and intrahepatic B/A ratios. The improved glucocorticoid homeostasis following SG, indicated by decreased B/A ratios, proposes a lower risk of glucocorticoid-mediated adverse health effects, including chronic kidney disease, hypertension, and metabolic disturbances.NEW & NOTEWORTHY This study revealed improved glucocorticoid homeostasis after sleeve gastrectomy (SG), with lower circulating ratios of active (corticosterone, B)/inactive (11-dehydrocorticosterone, A) glucocorticoids and a better glucose tolerance compared with Sham mice. SG enhanced renal HSD11B2 activity, whereas hepatic HSD11B1 oxoreductase activity was unchanged. These findings suggest that SG reverses some adverse metabolic effects of a high-fat diet by enhancing renal HSD11B2 activity, potentially lowering the risk of chronic kidney disease, hypertension, and metabolic disease.