1912-P: Bariatric Surgery Downregulates Glucocorticoid Signaling in Mice

Abstract

Background: Glucocorticoids (GC) produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis. GC activation is catalyzed by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and signalling is achieved through the glucocorticoid receptor (GR), a ligand-dependent transcription factor. Excess glucocorticoids are associated with insulin resistance and hyperglycaemia. A small number of studies have investigated the effects of bariatric surgery, a gastrointestinal procedure known to improve insulin sensitivity, on glucocorticoid metabolism, but the hypothesised mechanism is assumed to be via weight loss. Aim: To investigate the effect of bariatric surgery on glucocorticoid metabolism in lean and obese mice. Methods: Fourteen lean mice and twelve HFD mice underwent Vertical Sleeve Gastrectomy (VSG) (n=7-8) or sham (n=5-6) surgery. Glucose and insulin tolerance tests were performed four weeks post operatively. Liver, gut and adipose tissue were harvested from fed mice and analysed using Quantitative real-time PCR (qRT-PCR) and Western Blot (WB). Results: VSG did not cause excess weight loss in lean mice when compared to sham operated mice (p=0.37). However, both lean and HFD VSG mice displayed significantly improved glucose and insulin tolerance (p<0.001). Of note, qPCR and Western blotting analysis on mouse liver demonstrated a significant lowering of 11β-HSD1 levels 4 and 12 weeks after VSG (p<0.01). Additionally, in lean mice, 11β-HSD1 expression was also lowered in omental adipose tissue (p=0.01) and GR expression was inhibited in liver and ileum at the transcript level (p<0.05). Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoid activation physiologically and in the obese state, irrespective of weight loss. The reduction in glucocorticoid signalling may represent an additional contribution to the health benefits of bariatric surgery. These findings point towards a physiologically-relevant gut-adrenal axis. Disclosure E. Akalestou: None. L. Lopez Noriega: None. I. Christakis: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. Funding Rosetrees Foundation (M825); British Society for Neuroendocrinology; Society for Endocrinology (19ES001); UK Wellcome Trust (212625/Z/18/Z); Medical Research Council UK (MR/R022259/1); European Union (115881)