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 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.

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

“…A decrease in serum fatty acid levels has been reported following salicylate administration in rats20, 21, 43 and in healthy and diabetic humans 22, 44, 45, 46, 47. There is evidence that salicylates inhibit lipolysis and enhance fatty acid re‐esterification in animal adipose tissue ex‐vivo23, 48 and downregulate the expression and activity of adipose 11β‐hydroxysteroid dehydrogenase type 1, a lipolytic enzyme 24, 49. However, all previous studies have used high dose of salicylates (minimum 1 g per day for 4 days25, 44).…”

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

“…Interestingly, some studies suggest that antiinflammatory salicylates improve glucose metabolism in obese non-diabetic individuals [78]. In mice with dietinduced obesity, the insulin-sensitising effect of salicylate is associated with downregulation of 11βHSD1 expression and activity in visceral adipose tissue and is absent in 11βHSD1 knockout mice, suggesting that 11βHSD1 is a key mediator of the metabolic effects of salicylate [79]. In humans, salicylate also downregulates adipose 11βHSD1 expression, although this has yet to be demonstrated to mediate improved insulin sensitivity [79].…”

Inhibition of 11β-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice

“…Metabolic effects of the 11b-HSD1 inhibitor LG13 in the livers of type 2 diabetic mice Inhibition of 11b-HSD1 has been shown to improve serum lipid profiles and alleviate fatty liver in mice with metabolic syndrome or type 2 diabetes (Nixon et al 2012, Stewart & Tomlinson 2009). We next investigated whether LG13 treatment could attenuate such pathological changes.…”

“…Given that 11b-HSD1 is abundantly expressed in metabolically important tissues which become resistant to insulin action in type 2 diabetes, such as adipose, muscle, and liver tissue (Chapman et al 2013), inhibition of 11b-HSD1 offers the ability to restore the metabolic action of insulin in these tissues. Furthermore, the lowering of intracellular GC concentration through a variety of means, including the administration of small molecular 11b-HSD1 inhibitors, significantly attenuates the signs and symptoms of disease in animal models and in patients with diabetes/metabolic syndrome (Tahrani et al 2011, Nixon et al 2012, Harno et al 2013a. In recent decades, a number of small molecule inhibitors of 11b-HSD1 have been discovered, and several molecules have been evaluated in clinical trials.…”

“…Recent investigations have indicated that GC excess in tissues such as liver and adipose tissue contributes to the development of metabolic syndrome, whose characteristics include central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension (Masuzaki et al 2001, Morton et al 2005, Walker 2006, Macfarlane et al 2008. 11b-hydroxysteroid dehydrogenase (11b-HSD) type 1, which catalyses the conversion of active GCs (cortisol in humans and corticosterone in rodents) from their inactive 11-keto metabolites (cortisone in humans and 11-dehydrocorticosterone in rodents), can amplify the local level and activity of GCs (Masuzaki et al 2001, Nixon et al 2012, Chapman et al 2013. On the other hand, 11b-HSD2, as another isoform of 11b-HSDs, catalyzes the opposite reaction, converting corticosterone to 11-dehydrocorticosterone in rodents (Chapman et al 2013).…”