11-Beta hydroxysteroid dehydrogenaseThe systematic name of this enzyme class is 11beta-hydroxysteroid: This enzyme participates steroids za c steroid hormone metabolism and androgen 11 beta-hydroxysteroid dehydrogenase-1 or hsd estrogen metabolism. Cortisola glucocorticoid, binds the glucocorticoid receptor. However, because of its molecular similarity to aldosterone it is also capable of binding the mineralcorticoid receptor. Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, there is vastly more cortisol in circulation than aldosterone. In humans, there dehydrogenaee-1 two HSD11B isoforms: Inhibition of HSD11B1 has been suggested as a possible therapy for treatment of obesity and metabolic syndrome.
Beta hydroxysteroid dehydrogenase - an overview | ScienceDirect Topics
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The aim of this study is to identify these mechanisms in high fat diet HFD experimental models. Glucocorticoids are steroid hormones that bind to the glucocorticoid receptor GR and have powerful anti-inflammatory and immunosuppressive effects. However, patients treated with glucocorticoids develop obesity, insulin resistance, glucose intolerance, and dyslipidemia 1. Currently, more than 2.
As such, insulin resistance resulting from glucocorticoid exposure is becoming an important public health problem and there is an urgent need to understand the mechanisms by which glucocorticoids induce insulin resistance.
These enzymes carry out the interconversion of non-receptor binding cortisone and the receptor binding active form, cortisol. This suggests that high local levels of glucocorticoids, at least in adipocytes, promote an inflammatory rather than the expected anti-inflammatory activity through cortisol.
This inflammatory function of glucocorticoids may be regulated through c-Jun N-terminal kinases JNK , which is believed to be a central player in the insulin signaling in diabetes and insulin resistance. Reports show that JNK knockout mice are protected against the development of insulin resistance 12 , Moreover, administration of small molecule or peptide inhibitors of JNK significantly improved insulin sensitivity in insulin-resistant rodents 14 , Multiple factors can activate JNK, such as inflammatory cytokines and free fatty acids.
Importantly, glucocorticoids can also increase JNK activity in epithelial cells 16 , hippocampal cells 17 and endothelial cells For study, we used the high fat diet HFD mouse model and cultured adipocytes to investigate this potential pathophysiological mechanism under conditions of obesity. Our results show that mice fed with HFD have significantly increased body weights compared to the mice fed standard chow Fig.
Treatment of HFD mice with PF reduced weight gain compared to the mice treated with vehicle after 8 weeks The gels were run under the same experimental conditions. We also determined JNK activaton by measuring its phosphorylation in the mouse adipose tissues. As expected from our in vivo studies, treatment of 3T3-L1 pre-adipocytes with prednisone increased phosphorylation of JNK and this increase was abolished by PF and C66 Fig.
Cells were treated as in A and B. All the gels were run under the same experimental conditions. To evaluate the significance of this JNK activation pathway in development of insulin resistance, we determined the effects of C66 on prednisone-induced insulin resistance. Treatment of 3T3-L1-derived adipocytes with prednisone decreased insulin-stimulated glucose uptake Fig.
Glucose uptake rate was measured as described in the methods section. Representative blots from 3 independent experiments were shown. Glucose uptake rate h and Akt phosphorylation i were determined. As shown in Fig. Following insulin treatment, glucose uptake rate was calculated. The gels from Fig. Glucocorticoids are widely used in the clinic as anti-inflammatory agents for a number of human diseases including autoimmune diseases, cancer, organ rejection, and asthma.
However, glucocorticoids often lead to insulin resistance and diabetes, a condition referred to as steroid-induced diabetes. JNK then inhibits insulin-induced Akt phosphorylation leading to insulin resistance.
Adipose tissue plays an essential role in regulation of whole-body insulin sensitivity. And glucocorticoids have profound effects on the adipose tissue, such as driving central obesity by promoting the redistribution of fat from periphery to abdomen and inducing pre-adipocyte differentiation 26 , A potential limitation of our study is that we did not examine the liver tissues in these mice.
However, the mechanisms may be shared with adipocytes and may also involve JNK. Interestingly, specific suppression of JNK activation in adipose tissue alone is sufficient to prevent the development of insulin resistance in HFD mice JNK interferes with insulin signaling through several mechanisms. JNK activation in adipose tissue has also been shown to decrease the production of adiponectin, which contributes to insulin resistance induced by JNK activation 30 , Activation of JNK by glucocorticoids and its involvement in insulin signaling has been also reported by other groups in different systems.
We found that glucocorticoids activated JNK in adipocytes, resulting in aberrations in the insulin signaling pathway. However, the co-immunoprecipitation data could not rule out the existence of other linker proteins in the complex.
In addition, multiple lines of evidence have shown that glucocorticoids can directly activate protein kinase C PKC isoforms 17 , 39 , 40 , 41 , 42 , 43 which are upstream activators of JNK 44 , 45 , 46 , PKC activation has also been demonstrated to cause insulin resistance 48 , 49 , Overall, findings from our study strongly support a role of JNK activation in GC-induced insulin resistance.
Upon confluence, cells were trypsinized and plated onto culture dishes for the measurement of kinase phosphorylation, and protein expression and mRNA levels. Prednisone was incubated for the indicated time intervals. To induce the differentiation of 3T3-L1 cells into adipocytes, cells were cultured to confluence.
The amount of glucose taken up by the differentiated 3T3-L1 adipocytes cells was measured by determining the difference of glucose concentrations in the culture medium before and after incubation with cells. Glucose levels in the medium were measured using a glucose assay kit. Animals were housed with a The mice were acclimatized to the laboratory for at least 2 weeks before initiating studies.
After 8 weeks of diet intervention, the HFD mice were randomized to 3 groups for another 8 weeks of treatment as follows: Body weight measurements and oral glucose tolerance test OGTT were performed at the end of the treatment period. The subcutaneous adipose tissue was harvested for gene and protein expression analysis. Primers were obtained from Thermo Fisher. The membranes were pre-incubated for 1. Following primary antibody incubation, immunoreactive bands were detected by horseradish peroxidase-conjugated secondary antibodies and enhanced chemiluminescence reagents Bio-Rad, Hercules, CA.
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