Abstract:
Effects of glucocorticoids on metabolism are tied to mechanisms linked to insulin resistance, hyperglycemia and abnormal lipid levels, with glucocorticoid excess leading to increased circulating free fatty acids and lipid accumulation in skeletal muscle and liver [1-4]. Obese individuals exhibit higher activity of the hypothalamic-pituitary-adrenal (HPA) axis and increased expression of 11βhydroxysteroid dehydrogenase type 1 (11βHSD1; reactivating cortisol from cortisone and corticosterone from 11-dehydrocorticosterone) in adipose tissue [5, 6]. Mice overexpressing 11βHSD1 in adipose tissue were found to become obese, insulin resistant, dyslipidemic and hypertensive [7], while liver-specific 11βHSD1 overexpression leads to insulin resistance and hypertension but not obesity [8]. Roux-en-Y-Bypass surgery rapidly improves conditions such as type 2 diabetes, dyslipidemia, and hypertension, with substantial reductions in cardiovascular disease and death risk [10]. Woods et al. provided evidence for increased hepatic 11βHSD1 activity after Roux-en-Y-Bypass in severely obese patients based on an increased raised serum cortisol/cortisone ratio. However, subcutaneous adipose tissue 11βHSD1 activity was decreased, along with reduced total urinary cortisol metabolites, suggesting lowered HPA axis activity [5]. Decreased subcutaneous adipose tissue 11βHSD1 activity was also reported in humans one to two years post-gastric bypass surgery, along with positive changes in insulin sensitivity and peripheral glucocorticoid metabolism [11-13]. Others found that sleeve gastric surgery (SG) reinstated normal corticosterone production in mice fed a high-fat diet (HFD) and lowered 11βHSD1 expression in both liver and adipose tissue postsurgically [14]. Inhibition of 11βHSD1 holds potential for diabetes and obesity treatment. Selective 11βHSD1 inhibitors have shown promising results in mouse models, improving glucose intolerance, food intake, and decreased weight gain [13, 15, 16]. This study assessed the improvement of weight change and glucose tolerance after SG, comparing levels with those of a lean control fed with normal chow (lean control, LC). Additionally, changes in the expression of 11βHSD1 and hexose-6-phosphate dehydrogenase (H6PD; restoring NADPH for the oxoreductase activity of 11βHSD1) were assessed in epididymal white adipose tissue (WAT) and liver. In WAT, 11βHsd1 and H6pd mRNA expression tended to be higher in Sham than in LC, which was reversed after SG. A similar pattern was observed for the transcription factors CCAAT enhancer binding protein alpha and beta (Cebpa and Cebpb), known to regulate 11βHSD1 expression.. 11βHsd1 and H6pd mRNA expression was similarly increased in Sham compared to LC and reversed after SG in liver. Interestingly, 11βHSD1 protein expression was higher in LC than in Sham, with a trend decrease for SG vs Sham. H6PD protein expression pattern resembled that of mRNA. SG decreased Cebpa but not Cebpb mRNA. Measurements of the active glucocorticoid corticosterone and the inactive 11-dehydrocorticosterone in serum revealed higher glucocorticoid levels of LC compared to Sham, with a trend reversal after SG. The ratio of active to inactive glucocorticoids (B/A) showed the opposite pattern. Overall, the findings indicate an impaired glucocorticoid reactivation by 11βHSD1/H6PD and involvement of Cebpa and Cebpb in the regulation of their expression in these obese mice, with at least partial reversal after SG.
Audience take-away:
• Changes in corticosteroid homeostasis as a result of obesity.
• Effects of sleeve gastric surgery on enzymes involved in glucocorticoid reactivation in liver and white adipose tissue in mice.
• Targeting the glucocorticoid homeostasis, e.g. by 11βHSD1 inhibitors, as a potential treatment option for obesity.
