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Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization.

Diabetes (2012-02-24)
Mark Nixon, Deborah J Wake, Dawn E Livingstone, Roland H Stimson, Cristina L Esteves, Jonathan R Seckl, Karen E Chapman, Ruth Andrew, Brian R Walker
ABSTRACT

Recent trials show salicylates improve glycemic control in type 2 diabetes, but the mechanism is poorly understood. Expression of the glucocorticoid-generating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in adipose tissue is increased in vitro by proinflammatory cytokines and upregulated in obesity. 11β-HSD1 inhibition enhances insulin sensitivity. We hypothesized that salicylates downregulate 11β-HSD1 expression, contributing to their metabolic efficacy. We treated diet-induced obese (DIO) 11β-HSD1-deficient mice and C57Bl/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 (3)H-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 11β-HSD1 activity in vivo and adipose tissue 11β-HSD1 transcript levels ex vivo. In C57Bl/6 DIO mice, salicylate improved glucose tolerance and downregulated 11β-HSD1 mRNA and activity selectively in visceral adipose. DIO 11β-HSD1-deficient mice were resistant to these metabolic effects of salicylate. In men, salsalate reduced 11β-HSD1 expression in subcutaneous adipose, and in vitro salicylate treatment reduced adipocyte 11β-HSD1 expression and induced adiponectin expression only in the presence of 11β-HSD1 substrate. Reduced intra-adipose glucocorticoid regeneration by 11β-HSD1 is a novel mechanism that contributes to the metabolic efficacy of salicylates.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Sodium salicylate, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Sodium salicylate, meets USP testing specifications
Sigma-Aldrich
Sodium salicylate, puriss. p.a., reag. Ph. Eur., 99.5-101.0% (calc. to the dried substance)
Sigma-Aldrich
Sodium salicylate, tested according to Ph. Eur.
Sigma-Aldrich
Sodium salicylate, puriss. p.a., ≥99.5% (NT)
Sigma-Aldrich
Salsalate, ≥98% (HPLC)