Abstract
Glucocorticoids are used to treat a number of human diseases but often lead to insulin resistance and metabolic syndrome. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Despite the known role of 11β-HSD1 and active glucocorticoid in causing insulin resistance, the molecular mechanisms by which insulin resistance is induced remain elusive. The aim of this study is to identify these mechanisms in high fat diet (HFD) experimental models. Mice on a HFD were treated with 11β-HSD1 inhibitor as well as a JNK inhibitor. We then treated 3T3-L1-derived adipocytes with prednisone, a synthetic glucocorticoid, and cells with 11β-HSD1 overexpression to study insulin resistance. Our results show that 11β-HSD1 and JNK inhibition mitigated insulin resistance in HFD mice. Prednisone stimulation or overexpression of 11β-HSD1 also caused JNK activation in cultured adipocytes. Inhibition of 11β-HSD1 blocked the activation of JNK in adipose tissue of HFD mice as well as in cultured adipocytes. Furthermore, prednisone significantly impaired the insulin signaling pathway, and these effects were reversed by 11β-HSD1 and JNK inhibition. Our study demonstrates that glucocorticoid-induced insulin resistance was dependent on 11β-HSD1, resulting in the critical activation of JNK signaling in adipocytes.
Highlights
Our results show that mice fed with high fat diet (HFD) have significantly increased body weights compared to the mice fed standard chow (Fig. 1a)
Western blot analysis showed that HFD significantly increased the expression of both 11 β-HSD1 and glucocorticoid receptor (GR) in subcutaneous adipose tissues (Fig. 1d)
We assessed the adipose tissue of PF00915275- and C66-treated mice for expression of insulin receptor substrate 1 (IRS1), glucose transporter-4 (GLUT4), adiponectin and fatty acid binding protein (FABP) as indices of insulin sensitivity
Summary
The overexpression of 11β-HSD1 gene in adipose tissue can increase levels of leptin, resistin, tumor necrosis factor-α(TNF-α), and interleukin-6 (IL-6)[10,11]. This suggests that high local levels of glucocorticoids, at least in adipocytes, promote an inflammatory rather than the expected anti-inflammatory activity through cortisol. We hypothesized that glucocorticoid-induced insulin resistance is dependent on 11β-HSD1, resulting in critical activation of JNK in adipose tissue. Results indicate that glucocorticoid-induced insulin resistance was dependent on 11β-HSD1, resulting in the critical activation of JNK signaling in adipocytes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
