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- Title
Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization.
- Authors
Nixon, Mark; Wake, Deborah J.; Livingstone, Dawn E.; Stimson, Roland H.; Esteves, Cristina L.; Seckl, Jonathan R.; Chapman, Karen E.; Andrew, Ruth; Walker, Brian R.
- 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 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 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 C57B1/6 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.
- Subjects
SALICYLATES; GLYCEMIC index; TYPE 2 diabetes; GLUCOCORTICOIDS; HYDROXYSTEROID dehydrogenases; ADIPOSE tissues
- Publication
Diabetes, 2012, Vol 61, Issue 4, p790
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db11-0931