title: Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization.
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.
authors.affiliation: Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland, U.K. m.nixon@ed.ac.uk
authors.forename: Mark
authors.initials: M
authors.lastname: Nixon
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Wake
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Livingstone
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stimson
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Esteves
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation; D002460:Cell Line; D018592:Cross-Over Studies; D005786:Gene Expression Regulation / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D012980:Sodium Salicylate / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C014182:salicylsalicylic acid; D012980:Sodium Salicylate