scholarly journals Chronic Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity Decreases Hypertension, Insulin Resistance, and Hypertriglyceridemia in Metabolic Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Christine G. Schnackenberg ◽  
Melissa H. Costell ◽  
Daniel J. Krosky ◽  
Jianqi Cui ◽  
Charlene W. Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
Body Weight Gain ◽  
Plasma Renin ◽  
Hydroxysteroid Dehydrogenase ◽  
Common Mechanism ◽  
Metabolic Activities

Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11β-HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11β-HSD1. Compound 11 significantly decreased 11β-HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11β-HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome.

Hexose-6-phosphate dehydrogenase in the endoplasmic reticulum

2010 ◽  
Vol 391 (1) ◽  
Author(s):  
Silvia Senesi ◽  
Miklos Csala ◽  
Paola Marcolongo ◽  
Rosella Fulceri ◽  
Jozsef Mandl ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Endoplasmic Reticulum ◽  
Pentose Phosphate Pathway ◽  
Hydroxysteroid Dehydrogenase ◽  
Pyridine Nucleotide ◽  
Pentose Phosphate ◽  
The Metabolic Syndrome ◽  
Glucose 6 Phosphate Dehydrogenase

Abstract Hexose-6-phosphate dehydrogenase (H6PD) is a luminal enzyme of the endoplasmic reticulum that is distinguished from cytosolic glucose-6-phosphate dehydrogenase by several features. H6PD converts glucose-6-phosphate and NADP+ to 6-phosphogluconate and NADPH, thereby catalyzing the first two reactions of the pentose-phosphate pathway. Because the endoplasmic reticulum has a separate pyridine nucleotide pool, H6PD provides NADPH for luminal reductases. One of these enzymes, 11β-hydroxysteroid dehydrogenase type 1 responsible for prereceptorial activation of glucocorticoids, has been the focus of much attention as a probable factor in the pathomechanism of several human diseases including insulin resistance and the metabolic syndrome. This review summarizes recent advances related to the functions of H6PD.

scholarly journals Reduced Levels of Circulating 7α-Hydroxy-Dehydroepiandrosterone in Treated Adolescent Obese Patients

2014 ◽  
pp. 95-101
Author(s):  
L. MÁČOVÁ ◽  
M. BIČÍKOVÁ ◽  
H. ZAMRAZILOVÁ ◽  
M. HILL ◽  
H. KAZIHNITKOVÁ ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Mass Index ◽  
Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Obese Patients ◽  
Significant Difference ◽  
Before And After ◽  
Reductive Treatment ◽  
Circulating Levels

Elevated levels of glucocorticoids lead to the development of obesity and metabolic syndrome. Local glucocorticoid levels are regulated through the enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD 1), an enzyme that regenerates active cortisol from inert cortisone. Increased expression of 11β-HSD 1 in adipose tissue promotes higher body mass index (BMI), insulin resistance, hypertension, and dyslipidemia. Human 11β-HSD 1 is also responsible for inter-conversion of 7-hydroxylate metabolites of dehydroepiandrosterone (7-OH-DHEA) to their 7-oxo-form. To better understanding the mechanism of the action, we focused on 7-OH- and 7-oxo-DHEA, and their circulating levels during the reductive treatment in adolescent obese patients. We determined plasma levels of 7α-OH-DHEA, 7β-OH-DHEA, and 7-oxo-DHEA in 55 adolescent patients aged 13.04-15.67 years, BMI greater than 90th percentile. Samples were collected before and after one month of reductive therapy. Circulating levels of 7α-OH-DHEA decreased during the reductive therapy from 1.727 (1.614; 1.854, transformed mean with 95 % confidence interval) to 1.530 nmol/l (1.435; 1.637, p<0.05) in girls and from 1.704 (1.583; 1.842) to 1.540 nmol/l (1.435; 1.659, p<0.05) in boys. With regard to the level of 7-oxo-DHEA, a significant reduction from 1.132 (1.044; 1.231) to 0.918 nmol/l (0.844; 1.000, p<0.05) was found after the treatment, but only in boys. No significant difference in 7β-OH-DHEA levels was observed. In conclusions, diminished levels of 7α-OH-DHEA indicate its possible effect on activity of 11β-HSD 1. Further studies are necessary to clarify whether competitive substrates for 11β-HSD 1 such as 7α-OH-DHEA could inhibit production of glucocorticoids and may be involved in metabolic processes leading to reduction of obesity.

11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue and Prospective Changes in Body Weight and Insulin Resistance*

Obesity ◽  
2006 ◽  
Vol 14 (9) ◽  
pp. 1515-1522 ◽  
Author(s):  
Juraj Koska ◽  
Barbora de Courten ◽  
Deborah J. Wake ◽  
Saraswathy Nair ◽  
Brian R. Walker ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase

Suppression of 11beta-hydroxysteroid dehydrogenase type 1 activity diminish insulin resistance and hypertriglyceridemia in metabolic syndrome

2010 ◽  
Vol 34 (8) ◽  
pp. S30-S30
Author(s):  
Jianqi Cui ◽  
Christine G. Schnackenberg ◽  
Melissa H. Costell ◽  
Daniel J. Krosky ◽  
Charlene W. Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Hydroxysteroid Dehydrogenase

scholarly journals β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome

2013 ◽  
Vol 219 (3) ◽  
pp. 231-241 ◽  
Author(s):  
Liselotte Fransson ◽  
Stephanie Franzén ◽  
Victoria Rosengren ◽  
Petra Wolbert ◽  
Åke Sjöholm ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Drinking Water ◽  
Mouse Model ◽  
Glucose Intolerance ◽  
Body Weight Gain ◽  
Β Cell ◽  
Cell Adaptation ◽  
The Metabolic Syndrome ◽  
Islet Volume

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.

scholarly journals 11β-Hydroxysteroid dehydrogenase type 1 shRNA ameliorates glucocorticoid-induced insulin resistance and lipolysis in mouse abdominal adipose tissue

2015 ◽  
Vol 308 (1) ◽  
pp. E84-E95 ◽  
Author(s):  
Ying Wang ◽  
Chaoying Yan ◽  
Limei Liu ◽  
Wei Wang ◽  
Hanze Du ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Hydroxysteroid Dehydrogenase ◽  
Target Tissue ◽  
The Metabolic Syndrome ◽  
Lipid Metabolism Genes

Long-term glucocorticoid exposure increases the risk for developing type 2 diabetes. Prereceptor activation of glucocorticoid availability in target tissue by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH) is an important mediator of the metabolic syndrome. We explored whether the tissue-specific modulation of 11β-HSD1 and H6PDH in adipose tissue mediates glucocorticoid-induced insulin resistance and lipolysis and analyzed the effects of 11β-HSD1 inhibition on the key lipid metabolism genes and insulin-signaling cascade. We observed that corticosterone (CORT) treatment increased expression of 11β-HSD1 and H6PDH and induced lipase HSL and ATGL with suppression of p-Thr172 AMPK in adipose tissue of C57BL/6J mice. In contrast, CORT induced adipose insulin resistance, as reflected by a marked decrease in IR and IRS-1 gene expression with a reduction in p-Thr308 Akt/PKB. Furthermore, 11β-HSD1 shRNA attenuated CORT-induced 11β-HSD1 and lipase expression and improved insulin sensitivity with a concomitant stimulation of pThr308 Akt/PKB and p-Thr172 AMPK within adipose tissue. Addition of CORT to 3T3-L1 adipocytes enhanced 11β-HSD1 and H6PDH and impaired p-Thr308 Akt/PKB, leading to lipolysis. Knockdown of 11β-HSD1 by shRNA attenuated CORT-induced lipolysis and reversed CORT-mediated inhibition of pThr172 AMPK, which was accompanied by a parallel improvement of insulin signaling response in these cells. These findings suggest that elevated adipose 11β-HSD1 expression may contribute to glucocorticoid-induced insulin resistance and adipolysis.

scholarly journals Local and Systemic Impact of Transcriptional Up-Regulation of 11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity

2003 ◽  
Vol 88 (8) ◽  
pp. 3983-3988 ◽  
Author(s):  
Deborah J. Wake ◽  
Eva Rask ◽  
Dawn E. W. Livingstone ◽  
Stefan Söderberg ◽  
Tommy Olsson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Ex Vivo ◽  
Hydroxysteroid Dehydrogenase ◽  
Mrna Levels ◽  
Urinary Cortisol ◽  
Cortisol Metabolism ◽  
The Impact

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11β-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized β coefficient (SBC) = 0.58; P &lt; 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P &lt; 0.05 for activity, and SBC = 0.63; P &lt; 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P &lt; 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-α and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P &lt; 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P &lt; 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 ± 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

scholarly journals 11-Dehydrocorticosterone Causes Metabolic Syndrome, Which Is Prevented when 11β-HSD1 Is Knocked Out in Livers of Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3599-3609 ◽  
Author(s):  
Erika Harno ◽  
Elizabeth C. Cottrell ◽  
Brian G. Keevil ◽  
Joanne DeSchoolmeester ◽  
Mohammad Bohlooly-Y ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Body Weight Gain ◽  
Chronic Administration ◽  
Metabolic Effects ◽  
Hepatic Tissue ◽  
Intracellular Regeneration ◽  
Pituitary Adrenal Axis

Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which has led to investigation of the link between excess glucocorticoids and metabolic syndrome. Indeed, increased glucocorticoids from intracellular regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesized that increasing the substrate for 11β-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal axis. This elevated 11β-HSD1-derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprisingly liver-specific 11β-HSD1 knockout (LKO) mice given 11-DHC did not show any of the adverse metabolic effects seen in wild-type mice. This occurred despite the 11-DHC administration resulting in elevated circulating corticosterone, presumably from adipose tissue. Mice with global deletion of 11β-HSD1 (global knockout) were unaffected by treatment with 11-DHC, having no increase in circulating corticosterone and exhibiting no signs of metabolic impairment. Taken together, these data show that in the absence of 11β-HSD1 in the liver, mice are protected from the metabolic effects of 11-DHC administration, even though circulating glucocorticoids are increased. This implies that liver-derived intratissue glucocorticoids, rather than circulating glucocorticoids, contribute significantly to the development of metabolic syndrome and suggest that local action within hepatic tissue mediates these effects.

scholarly journals Proinflammatory Cytokine Induction of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) in Human Adipocytes Is Mediated by MEK, C/EBPβ, and NF-κB/RelA

2014 ◽  
Vol 99 (1) ◽  
pp. E160-E168 ◽  
Author(s):  
Cristina L. Esteves ◽  
Val Kelly ◽  
Amandine Breton ◽  
Ashley I. Taylor ◽  
Christopher C. West ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Acetylsalicylic Acid ◽  
Proinflammatory Cytokines ◽  
Hydroxysteroid Dehydrogenase ◽  
Low Grade ◽  
Mrna Levels ◽  
Human Adipocytes ◽  
Cytokine Induction

Context: Levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids, are selectively elevated in adipose tissue in human obesity and metabolic syndrome, both conditions associated with chronic low-grade inflammation. 11β-HSD1 expression is induced by proinflammatory cytokines in a variety of cell types, including in human adipocytes differentiated in vitro. Objective: Our objective was to determine the mechanisms by which proinflammatory cytokines induce 11β-HSD1 in human adipocytes. Results: The proinflammatory cytokines IL-1α (10 ng/mL) and TNFα (20 ng/mL) increased 11β-HSD1 mRNA levels in human primary adipocyte fractions and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes (P &lt; .001). Inhibition of the MAPK/ERK kinase (MEK) attenuated CCAAT/enhancer binding protein (C/EBP) β phosphorylation at Thr235 and IL-1α/TNFα induction of 11β-HSD1 (P ≤ .007). The small interfering RNA-mediated knockdown of C/EBPβ and nuclear factor (NF)-κB/RelA or inhibition of NF-κB/RelA also attenuated cytokine induction of 11β-HSD1 (P ≤ .001). Moreover, induction of 11β-HSD1 by IL-1α in SGBS cells was associated with nuclear localization of C/EBPβ and NF-κB/RelA. Chromatin immunoprecipitation experiments showed C/EBPβ and NF-κB/RelA located to the 11β-HSD1 promoter in human adipose tissue. Treatment of adipocyte fractions or SGBS adipocytes with metformin or acetylsalicylic acid, which target C/EBPβ and NF-κB/RelA signaling, attenuated the IL-1α induction of 11β-HSD1 (P ≤ .002). Conclusions: Increased proinflammatory signaling in inflamed adipose tissue may mediate elevated 11β-HSD1 expression at this site via MEK, C/EBPβ, and NF-κB/RelA. These molecules/signaling pathways are, therefore, potential targets for drugs, including metformin and acetylsalicylic acid, to prevent/decreased up-regulation of 11β-HSD1 in human obese/metabolic syndrome adipose tissue.

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