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

Diabetes. 2012 Apr;61(4):790-6. doi: 10.2337/db11-0931. Epub 2012 Feb 22.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / physiology
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Adult
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Body Weight / drug effects
  • Cell Differentiation
  • Cell Line
  • Cross-Over Studies
  • Gene Expression Regulation / drug effects*
  • Glucose Tolerance Test
  • Humans
  • Insulin Resistance / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Obesity / metabolism*
  • Salicylates / pharmacology
  • Sodium Salicylate / pharmacology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Salicylates
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • salicylsalicylic acid
  • Sodium Salicylate