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 Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

2014 ◽  
Vol 111 (10) ◽  
pp. 3817-3822 ◽  
Author(s):  
Ananda Chapagain ◽  
Paul W. Caton ◽  
Julius Kieswich ◽  
Petros Andrikopoulos ◽  
Nanda Nayuni ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Hydroxysteroid Dehydrogenase ◽  
Metabolic Disturbances ◽  
Intracellular Regeneration ◽  
Rat Models ◽  
Hepatic Expression ◽  
Lipogenic Genes ◽  
Subtotal Nephrectomy

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

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 Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

2020 ◽  
Author(s):  
Yujeong Kim ◽  
Ok-Kyung Kim
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Metabolic Disorders ◽  
Extracellular Vesicle ◽  
Extracellular Mirnas

ABSTRACT Recently, extracellular microRNAs (miRNAs) from adipose tissue have been shown to be involved in the development of insulin resistance. Here, we summarize several mechanisms explaining the pathogenesis of obesity-induced insulin resistance and associated changes in the expression of obesity-associated extracellular miRNAs. We discuss how miRNAs, particularly miR-27a, miR-34a, miR-141-3p, miR-155, miR210, and miR-222, in extracellular vesicles secreted from the adipose tissue can affect the insulin signaling pathway in metabolic tissue. Understanding the role of these miRNAs will further support the development of therapeutics for obesity and metabolic disorders such as type 2 diabetes.

Beta-sitosterol attenuates insulin resistance in adipose tissue via IRS-1/Akt mediated insulin signaling in high fat diet and sucrose induced type-2 diabetic rats

2020 ◽  
Vol 873 ◽  
pp. 173004 ◽  
Author(s):  
Shyamaladevi Babu ◽  
Madhan Krishnan ◽  
Ponnulakshmi Rajagopal ◽  
Vijayalakshmi Periyasamy ◽  
Vishnupriya Veeraraghavan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Diabetic Rats ◽  
High Fat ◽  
Type 2 Diabetic

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

2013 ◽  
Vol 15 (2) ◽  
Author(s):  
Roland H. Stimson ◽  
Brian R. Walker
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Selective Inhibition ◽  
Hydroxysteroid Dehydrogenase ◽  
The Metabolic Syndrome ◽  
Specific Regulation ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

AbstractThe cortisol regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11β-HSD1; consequently, selective 11β-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11β-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11β-HSD1. These results have been surprising, as cortisol production rates by 11β-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11β-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11β-HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11β-HSD1 inhibitors are likely to be an important new therapy for metabolic disease.

scholarly journals Effects of Peroxisome Proliferator-Activated Receptor-α and -γ Agonists on 11β-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men

2007 ◽  
Vol 92 (5) ◽  
pp. 1848-1856 ◽  
Author(s):  
Deborah J. Wake ◽  
Roland H. Stimson ◽  
Garry D. Tan ◽  
Natalie Z. M. Homer ◽  
Ruth Andrew ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Cortisol ◽  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Cortisol Secretion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Healthy Men ◽  
Pparγ Agonists

Abstract Context: In animals, peroxisome proliferator-activated receptor-α (PPARα) and PPARγ agonists down-regulate 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARγ agonists reduce ACTH secretion from corticotrope cells. Objective: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11β-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARγ agonists. Design and Setting: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. Patients and Participants: Healthy men and patients with type 2 diabetes participated. Interventions, Outcome Measures, and Results: In nine healthy men, 7 d of PPARα agonist (fenofibrate) or PPARγ agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[2H]4-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4–5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11β-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11β-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. Conclusions: Neither PPARα nor PPARγ agonists down-regulate 11β-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11β-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.

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 Stress during Lactation Induces Insulin Resistance Associated with an Increase in Type 1 Cannabinoid Receptors in Liver and Adipose Tissue

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Liza Fonseca ◽  
Valeska Castillo ◽  
Carolina Aguirre ◽  
Paulo Silva ◽  
Ana M. Ronco ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cannabinoid Receptors ◽  
Tolerance Test ◽  
Epididymal Adipose Tissue ◽  
Adult Mice ◽  
Epididymal Fat ◽  
Circulating Levels

Several reports have shown that stress during lactation causes long-term metabolic and hormonal disruptions. In this study, we designed experiments to evaluate the effects of stress during lactation on the abundance of Type 1 cannabinoid/endocannabinoid receptors (CB1R) in epididymal fat and liver and development of insulin resistance in adult mice. During the whole lactation, male mice pups were daily subcutaneously injected (days 1–21) with a saline solution to produce a soft nociceptive stress (NS). Mice body weight and food intake were periodically evaluated. Adult animals were subsequently subjected to an insulin tolerance test and some days later sacrificed to evaluate the amount of epididymal fat and abundance of CB1R and adipophilin in liver and epididymal adipose tissue. Lipoprotein lipase (LPL) activity and circulating levels of leptin, adiponectin, and corticosterone were also evaluated. In this model, NS during lactation significantly increased the amount of epididymal fat and induced insulin resistance in adult mice. In addition, a significantly increased abundance of CB1R and adipophilin in epididymal fat and liver was observed, together with elevated circulating levels of leptin and corticosterone. Adult NS animals also had low plasmatic adiponectin and, although nonsignificant, had a sustained trend to a greater LPL activity associated with epididymal fat. These results indicate that increased abundance of CB1R in liver and epididymal fat alters tissue functionality likely associated with development of systemic metabolic alterations such as insulin resistance in adult mice. All these pathophysiological facts are long-term consequences of nociceptive stress during lactation.

Sign in / Sign up

Export Citation Format

Share Document