Expression and Activity of 11β-Hydroxysteroid Dehydrogenase Type 1 Enzyme in Subcutaneous and Visceral Adipose Tissue of Prepubertal Children

Abstract We examined the expression and activity of two enzymes from the aldoketoreductase (AKR) family 1C, namely type 5 17β-hydroxysteroid dehydrogenase (17β-HSD-5, AKR1C3) and type 3 3α-hydroxysteroid dehydrogenase (3α-HSD-3, AKR1C2) in female sc and omental adipose tissue and in preadipocyte primary cultures. 17β-HSD-5 preferentially synthesizes testosterone from the inactive adrenal precursor androstenedione, whereas 3α-HSD-3 inactivates dihydrotestosterone. mRNAs of both enzymes were detected in adipose tissue from the omental and sc compartments. Real-time PCR quantification indicated a 3-fold higher 3α-HSD-3 expression compared with 17β-HSD-5, and the expression of both enzymes tended to be higher in the sc vs. the omental depot. Accordingly, dose-response and time-course experiments performed in preadipocyte primary cultures indicated that 3α-HSD activity was higher than 17β-HSD activity (13-fold maximum velocity difference). We measured 3α-HSD activity in omental and sc adipose tissue samples of 32 women for whom body composition and body fat distribution were evaluated by dual-energy x-ray absorptiometry and CT, respectively. We found that androgen inactivation in omental adipose tissue through 3α-HSD activity was significantly higher in women with elevated vs. low visceral adipose tissue accumulation (1.7-fold difference; P < 0.05). Moreover, omental adipose tissue 3α-HSD activity was positively and significantly associated with CT-measured visceral adipose tissue (r = 0.43; P < 0.02) and omental adipocyte diameter (r = 0.42; P < 0.02). These results indicate that local androgen inactivation is a predominant reaction in female abdominal adipose tissue, with the greatest conversion rates observed in the presence of abdominal visceral obesity. Increased androgen inactivation in omental adipose tissue of abdominally obese women may impact locally on the regulation of adipocyte metabolism.

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Involvement of adipose tissue inflammation and dysfunction in virus-induced type 1 diabetes

Journal of Endocrinology ◽

10.1530/joe-18-0131 ◽

2018 ◽

Vol 238 (1) ◽

pp. 61-75 ◽

Cited By ~ 1

Author(s):

James C Needell ◽

Madalyn N Brown ◽

Danny Zipris

Keyword(s):

Type 1 Diabetes ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Poly I:C ◽

Adipose Tissue Inflammation ◽

Β Cell ◽

Tissue Inflammation ◽

Macrophage Recruitment ◽

Visceral Adipose

The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas β cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering β cell autoimmunity.

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

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0015 ◽

2013 ◽

Vol 15 (2) ◽

Cited By ~ 8

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.

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Human visceral adipose tissue and the plasminogen activator inhibitor type 1

International Journal of Obesity ◽

10.1038/sj.ijo.0803650 ◽

2007 ◽

Vol 31 (11) ◽

pp. 1671-1679 ◽

Cited By ~ 18

Author(s):

J H N Lindeman ◽

H Pijl ◽

K Toet ◽

P H C Eilers ◽

B van Ramshorst ◽

...

Keyword(s):

Adipose Tissue ◽

Plasminogen Activator ◽

Visceral Adipose Tissue ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor Type ◽

Inhibitor Type ◽

Activator Inhibitor Type ◽

Visceral Adipose ◽

Activator Inhibitor

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Visceral Adipose Tissue: A New Target Organ in Virus-Induced Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2021.702506 ◽

2021 ◽

Vol 12 ◽

Author(s):

Danny Zipris

Keyword(s):

Type 1 Diabetes ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Stress Responses ◽

Causal Role ◽

Β Cell ◽

Proinflammatory Response ◽

Adaptive Immune Cells ◽

Visceral Adipose

Type 1 diabetes (T1D) is a proinflammatory pathology that leads to the specific destruction of insulin producing β-cells and hyperglycaemia. Much of the knowledge about type 1 diabetes (T1D) has focused on mechanisms of disease progression such as adaptive immune cells and the cytokines that control their function, whereas mechanisms linked with the initiation of the disease remain unknown. It has been hypothesized that in addition to genetics, environmental factors play a pivotal role in triggering β-cell autoimmunity. The BioBreeding Diabetes Resistant (BBDR) and LEW1.WR1 rats have been used to decipher the mechanisms that lead to virus-induced T1D. Both animals develop β-cell inflammation and hyperglycemia upon infection with the parvovirus Kilham Rat Virus (KRV). Our earlier in vitro and in vivo studies indicated that KRV-induced innate immune upregulation early in the disease course plays a causal role in triggering β-cell inflammation and destruction. Furthermore, we recently found for the first time that infection with KRV induces inflammation in visceral adipose tissue (VAT) detectable as early as day 1 post-infection prior to insulitis and hyperglycemia. The proinflammatory response in VAT is associated with macrophage recruitment, proinflammatory cytokine and chemokine upregulation, endoplasmic reticulum (ER) and oxidative stress responses, apoptosis, and downregulation of adipokines and molecules that mediate insulin signaling. Downregulation of inflammation suppresses VAT inflammation and T1D development. These observations are strikingly reminiscent of data from obesity and type 2 diabetes (T2D) in which VAT inflammation is believed to play a causal role in disease mechanisms. We propose that VAT inflammation and dysfunction may be linked with the mechanism of T1D progression.

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