Objectives: Glucocorticoids produced by the adrenal cortex are essential for the maintenance of metabolic homeostasis.
Glucocorticoid activation is catalysed by 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1). Excess glucocorticoids are associated
with insulin resistance and hyperglycaemia. A small number of studies have demonstrated effects on glucocorticoid metabolism of
bariatric surgery, a group of gastrointestinal procedures known to improve insulin sensitivity and secretion, which were assumed
to result from weight loss. In this study, we hypothesize that a reduction in glucocorticoid action following bariatric surgery
contributes to the widely observed euglycemic effects of the treatment. Methods: Glucose and insulin tolerance tests were
performed at ten weeks post operatively and circulating corticosterone was measured. Liver and adipose tissues were harvested
from fed mice and 11β‐HSD1 levels were measured by quantitative RT‐PCR or Western (immuno‐) blotting, respectively. 11β‐HSD1
null mice (Hsd11b1-/-) were generated using CRISPR/ Cas9 genome editing. Wild type (WT) and littermate Hsd11b1-/- mice
underwent Vertical Sleeve Gastrectomy (VSG) or sham surgery. Results: WT VSG-treated mice displayed significantly improved
glucose tolerance versus sham controls, and this effect was observed in both regular chow- and HFD-fed animals. VSG lowered body
weight in HFD but not regular chow-fed mice. Remarkably, VSG restored physiological corticosterone production in HFD mice and
reduced 11β‐HSD1 expression in liver and adipose tissue post‐surgery. Elimination of the 11β‐HSD1/Hsd11b1 gene mimicked the
effects of VSG on body weight and tolerance to 1g/kg glucose challenge. However, at 3 g/kg glucose, the impact of VSG on glucose
excursion was indistinguishable between WT and Hsd11b1-/- mice, suggesting that the euglycemic effect of VSG was superior to
Hsd11b1 elimination. Conclusions: Bariatric surgery improves insulin sensitivity and reduces glucocorticoid activation at the
tissular level, under physiological and pathophysiological (obesity) conditions, irrespective of weight loss. These findings point
towards a physiologically relevant gut-glucocorticoid axis, and suggest that lowered glucocorticoid exposure may represent an
additional contribution to the health benefits of bariatric surgery.