Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11 beta-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11 beta-HSDI expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11 beta-HSD1-deficient mice and C57B1/6 mice with sodium salicylate for 4 weeks. Glucose tolerance was assessed in vivo. Tissue transcript levels were assessed by quantitative PCR and enzyme activity by incubation with H-3-steroid. Two weeks' administration of salsalate was also investigated in a randomized double-blind placebo-controlled crossover study in 16 men, with measurement of liver 11 beta-HSD1 activity in vivo and adipose tissue 11 beta-HSD1 transcript levels ex vivo. In C57B1/6 DIO mice, salicylate improved glucose tolerance and downregulated 11 beta-HSD1 mRNA and activity selectively in visceral adipose. DIO 11 beta-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11 beta-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11 beta-HSD1 expression and induced adiponectin expression only in the presence of 11 beta-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11 beta-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates. Diabetes 61:790-796, 2012