Endocrine Abstracts

Anti-inflammatory salicylates improve insulin sensitivity, however the mechanism remains unclear. We have observed down-regulation of the glucocorticoid regenerating enzyme 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) by salicylates in cultured adipocytes and in human adipose tissue after oral salsalate therapy, consistent with known transcriptional regulation of 11βHSD1 by pro-inflammatory cytokines. Since inhibition of 11βHSD1 improves insulin sensitivity, we have tested whether the insulin sensitising effects of salicylates are underpinned by reducing adipose 11βHSD1 in mice.

Male C57BL/6 mice (8 weeks) were studied after 10 weeks high-fat diet (58% fat with sucrose). Male homozygous 11βHSD1 knockout mice (HSD1KO) were also studied on the high-fat diet, weight-matched with obese wild type mice. Groups received either sodium salicylate (120 mg/kg per day, 4 weeks subcutaneously) or vehicle (n=8/treatment). Insulin sensitivity was assessed by glucose tolerance tests (i.p. GTT), after 3 weeks treatment. Plasma biochemical indices were quantified by spectrophotometry and transcripts by qPCR (relative expression). Data are mean±S.E.M.; vehicle versus salicylate, *P<0.05.

In wild type mice, salicylate decreased transcripts of tumor necrosis factor-alpha (1.19±0.14 vs 0.71±0.16*), 11βHSD1 (1.22±0.14 vs 0.72±0.16*), lipoprotein lipase (1.48±0.17 vs 0.45±0.15*) and adipose triglyceride lipase (1.39±0.22 vs 0.57±0.13*) in omental adipose, caused a redistribution of fat from omental to subcutaneous depots (ratio subcutaneous:omental 7.64±0.94 vs 11.29±1.07*), improved glucose tolerance (30%* reduction in area under curve for glucose) and resulted in greater post-prandial suppression of non-esterified fatty acids (23.33±3.46 vs 44.26±2.73%*). In contrast, in HSD1KO mice, salicylate did not cause a redistribution of fat (ratio subcutaneous:omental 12.87±1.89 vs 13.91±2.49) or improve glucose tolerance (no significant change in area under curve for glucose; 34.3±0.73 (g/dl).min versus 34.5±1.62 (g/dl).min).

We conclude that down-regulation of 11βHSD1 is crucial in the insulin sensitising mechanism of salicylate in obesity.