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

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 < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 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 < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 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 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.

scholarly journals Adipose tissue-targeted 11β-hydroxysteroid dehydrogenase type 1 inhibitor protects against diet-induced obesity

2011 ◽  
Vol 58 (3) ◽  
pp. 199-209 ◽  
Author(s):  
Juan Liu ◽  
Long Wang ◽  
Aisen Zhang ◽  
Wenjuan Di ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Diet Induced Obesity

Overexpression of hepatic 5α-reductase and 11β-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue is associated with hyperinsulinemia in morbidly obese patients

Metabolism ◽  
2011 ◽  
Vol 60 (12) ◽  
pp. 1775-1780 ◽  
Author(s):  
René Baudrand ◽  
José Miguel Domínguez ◽  
Cristian A. Carvajal ◽  
Arnoldo Riquelme ◽  
Carmen Campino ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Visceral Adipose

Abstract 6260: Up-Regulated Expression of MicroRNA-143 in Association with Obesity in the Adipose Tissue of Mice Fed High Fat Diet

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Rieko Takanabe ◽  
Koh Ono ◽  
Tomohide Takaya ◽  
Takahiro Horie ◽  
Hiromichi Wada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Control Cell ◽  
High Fat ◽  
Expression Levels ◽  
Mesenteric Fat ◽  
Regulated Expression

Obesity is the result of an expansion and increase in the number of individual adipocytes. Since changes in gene expression during adipocyte differentiation and hypertrophy are closely associated with insulin resistance and cardiovascular diseases, further insight into the molecular basis of obesity is needed to better understand obesity-associated diseases. MicroRNAs (miRNAs) are approximately 17–24nt single stranded RNA, that post-transcriptionally regulate gene expression. MiRNAs control cell growth, differentiation and metabolism, and may be also involved in pathogenesis and pathophysiology of diseases. It has been proposed that miR-143 plays a role in the differentiation of preadipocytes into mature adipocytes in culture. However, regulated expression of miR-143 in the adult adipose tissue during the development of obesity in vivo is unknown. To solve this problem, C57BL/6 mice were fed with either high-fat diet (HFD) or normal chow (NC). Eight weeks later, severe insulin resistance was observed in mice on HFD. Body weight increased by 35% and the mesenteric fat weight increased by 3.3-fold in HFD mice compared with NC mice. We measured expression levels of miR-143 in the mesenteric fat tissue by real-time PCR and normalized with those of 5S ribosomal RNA. Expression of miR-143 in the mesenteric fat was significantly up-regulated (3.3-fold, p<0.05) in HFD mice compared to NC mice. MiR-143 expression levels were positively correlated with body weight (R=0.577, p=0.0011) and the mesenteric fat weight (R=0.608, p=0.0005). We also measured expression levels in the mesenteric fat of PPARγ and AP2, whose expression are deeply involved in the development of obesity, insulin resistant and arteriosclerosis. The expression levels of miR-143 were closely correlated with those of PPARγ (R=0.600, p=0.0040) and AP2 (R=0.630, p=0.0022). These findings provide the first evidence for up-regulated expression of miR-143 in the mesenteric fat of HFD-induced obese mice, which might contribute to regulated expression of genes involved in the pathophysiology of obesity.

scholarly journals Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-α

2007 ◽  
Vol 97 (2) ◽  
pp. 389-398 ◽  
Author(s):  
Patricia Pérez-Matute ◽  
Nerea Pérez-Echarri ◽  
J. Alfredo Martínez ◽  
Amelia Marti ◽  
María J. Moreno-Aliaga
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Control Diet ◽  
Cafeteria Diet ◽  
High Fat ◽  
Beneficial Effects

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0·09), a decrease in food intake (P < 0·01) and an increase in leptin production (P < 0·05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0·05) which could be secondary to the inhibition of the adipogenic transcription factor PPARγ gene expression (P < 0·001), and also to the increase in apoptosis (P < 0·05) found in rats fed with a control diet. TNFα gene expression was significantly increased (P < 0·05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0·01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFα and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.

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