Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization
- Mark Nixon⇓,
- Deborah J. Wake,
- Dawn E. Livingstone,
- Roland H. Stimson,
- Cristina L. Esteves,
- Jonathan R. Seckl,
- Karen E. Chapman,
- Ruth Andrew and
- Brian R. Walker
- Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland, U.K.
- Corresponding author: Mark Nixon, .
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 3H-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.
- Received July 4, 2011.
- Accepted December 21, 2011.
- © 2012 by the American Diabetes Association.
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