Modulation of 11β-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers

Friedberg, Mark W.; Zoumakis, Emmanouil; Hiroi, Naoki; Bader, Tarif; Chrousos, George P.; Hochberg, Zèev

doi:10.1210/jc.2002-020510

Cited by 72 publications

(56 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All proinflammatory cytokines tested increased DHC-induced apoptosis, suggesting an increase in expression levels and reductase activity of 11␤-HSD1. Later effects have been observed in a rat embryonic cell line (10) and in adipocytes (14). Consequently, in an inflammatory condition associated with severe stress, the GC action can be amplified at the cellular level by an increase of 11␤-HSD1 expression or activity under the influence of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 98%

Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

D’Elia¹,

Patenaude²,

Bernier³

2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Glucocorticoids (GC) are important steroid hormones that regulate metabolism, development, and the immune system. GC are produced continuously, and maximal levels are reached following stress-related stimuli. Previous studies have demonstrated that increased GC production following thermal injury was responsible for thymic involution. Although GC are mainly synthesized by the adrenal glands, there is increasing evidence that GC may also be produced in nonadrenal tissues. The thymus was reported to express steroidogenic enzymes and to release GC. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is predominantly a reductase in cells and is essential for the local reactivation of GC. Here, we report that increased GC-induced apoptosis in thymocytes from burn-injured mice is related to increased glucocorticoid receptor (GR) expression and 11β-HSD1 expression in thymocytes at day 1 postburn injury. In vitro, thymocytes were able to convert 11-dehydrocorticosterone (DHC) to corticosterone (CORT), which induced their apoptosis, and this was pharmacologically inhibited by 18β-glycyrrhetinic acid, a specific 11β-HSD inhibitor. Moreover, 11β-HSD1 expression was confirmed in the 267S3 thymoma-derived cell line, and its activity was responsible for greater sensitivity of these cells to CORT-induced apoptosis. Finally, proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1β, and IL-6] increased thymocyte sensitivity to DHC-induced apoptosis through a mechanism involving 11β-HSD1. Overall, we have shown that burn injury induced 11β-HSD1 expression in thymocytes, which led to a greater sensitivity of these cells to CORT-induced apoptosis. Increased expression of 11β-HSD1 and GR may play a role in intrathymic T cell development and can be major determinants of GC sensitivity after a trauma.

show abstract

Section: Discussionmentioning

confidence: 98%

Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

D’Elia¹,

Patenaude²,

Bernier³

2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…36 Finally, we reported that in SAT, TNFa expression increased in parallel with 11b-HSD1 expression and this is in keeping with the evidence that TNFa increases 11b-HSD1 transcription in human adipose tissue. 37,38 The hypothesized decrease in adiponectin release would contribute to increase TNFa mRNA levels due to the hampering effect of this protein on TNFa transcription. 39 In conclusion, our study showed that in obese subjects, increased 11b-HSD1 expression in SAT, but not in VAT, is associated with the worsening of metabolic conditions.…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes and metabolic syndrome are associated with increased expression of 11β-hydroxysteroid dehydrogenase 1 in obese subjects

et al. 2007

View full text Add to dashboard Cite

Objective: The role of glucocorticoids production in adipose tissue in the development of metabolic disorders in humans has not been fully characterized. We investigated whether in obese subjects, 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) expression in subcutaneous (SAT) and visceral (VAT) adipose tissue is associated with the occurrence of metabolic disorders and the expression of adiponectin and tumor necrosis factor a (TNFa) and two glucocorticoid-regulated adipokines able to influence the metabolic control. Design and subjects: Sixty-two obese patients were enrolled in the study. SAT and VAT samples were obtained from 13 patients undergoing bariatric surgery (body mass index (BMI) 39.175.3 kg/m 2 ). SAT samples were obtained from 49 patients who underwent periumbilical biopsy (BMI 36.975.1 kg/m 2 ). Measurements: Oral glucose tolerance tests in subjects without known diabetes. Circulating glucose, lipid, insulin, adiponectin, TNFa and urinary-free cortisol levels. Real-time PCR to quantify mRNA levels of 11b-HSD1, hexose-6-phosphate dehydrogenase (H6PDH), adiponectin and TNFa. Western blot analysis to evaluate 11b-HSD1 protein expression. Results: In the majority of the obese subjects, VAT expresses more 11b-HSD1 than SAT. VAT 11b-HSD1 expression was not associated with metabolic disorders. SAT 11b-HSD1 mRNA levels were higher in subjects with than in those without metabolic syndrome (Po0.05) and in patients with type 2 diabetes compared to patients with impaired or normal glucose tolerance (Po0.0001). SAT 11b-HSD1 expression was independently related to fasting glucose (Po0.0001) and urinary-free cortisol levels (Po0.01), and increased expression of 11b-HSD1 was associated with increased adiponectin and TNFa expression and decreased serum adiponectin levels (all P's o0.05). Conclusions: In obese subjects, increased 11b-HSD1 expression in SAT, but not in VAT, is associated with the worsening of metabolic conditions. We hypothesize that higher glucocorticoid production in adipose tissue would favor the development of metabolic disorders through a decrease in adiponectin release.

show abstract

“…Among other regulatory mechanisms of enzyme activity (27), GH inhibits 11␤-HSD-1 activity and gene expression, while GH deficiency is associated with enhanced enzyme activity (28 -31).…”

mentioning

confidence: 99%

11β–Hydroxysteroid Dehydrogenase Type 1 Activity in Short Small-For-GA Children and in Response to GH Therapy

et al. 2011

View full text Add to dashboard Cite

Small for GA (SGA) children are at risk for developing the metabolic syndrome. Those who do not catch up, and remain short (SSGA), may benefit from GH therapy. 11␤ Hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) is expressed in visceral fat and is implicated in metabolic morbidity. We hypothesized that SSGA children will have increased basal and glucocorticoid (GC)-stimulated 11␤-HSD-1 activity. Twenty SSGA children, aged 7.1 Ϯ 1 y (mean Ϯ SD), were studied before and while on GH therapy and compared with 12 normal age-matched controls. 11␤-HSD-1 activity was evaluated by gas chromatography mass spectrometry (GCMS) of urinary steroid product/substrate ratios. GC-stimulated 11␤-HSD-1 activity was assessed after overnight dexamethazone (DEX), by oral cortisone conversion to cortisol. In SSGA children, 11␤-HSD-1 activity was lower (p Ͻ 0.05) and GC-stimulated activity enhanced. SSGA children had maximal cortisol generation of 883 Ϯ 108 compared with 690 Ϯ 63 nmol/L in controls (p Ͻ 0.04). GH treatment suppressed 11␤-HSD-1 activity. GC-stimulated enzyme activity correlated negatively with GA (r ϭ Ϫ0.53, p Ͻ 0.01) and birth weight (r ϭ Ϫ0.55, p Ͻ 0.01). SSGA is associated with enhanced GC-stimulated 11␤-HSD-1 activity. This may be programmed in utero, as it is not a function of body composition or secondary metabolic derangement. GH therapy normalizes GCstimulated 11␤-HSD-1 activity. (Pediatr Res 70: 208-212, 2011) B y definition, 5-10% of all neonates are born small for GA (SGA). Some of these children do not catch up (1,2) and remain short. They may benefit from GH therapy (3-5). This subgroup is designated in this article as short SGA (SSGA). Regardless of their later growth pattern, SGA children are at risk for developing the metabolic syndrome later in life (6 -10). This increased risk for future morbidity has been documented more in SGA individuals who had catch up growth (11-13), than in those who did not (14 -16).Fetal programming might be coupled with several endocrine pathways (17), including the hypothalamic-pituitaryadrenal (HPA) axis (18 -20). Indeed, elevated cortisol levels have been reported for adults born SGA (21) and in SSGA children (22)(23)(24). Elevated cortisol levels may also be involved in pre-and postnatal growth, as demonstrated by the inverse correlation between cortisol levels in cord blood and embryo length gained during the first trimester in intrauterine growth retarded (IUGR) children (25) .Prereceptor modulation of cortisol by 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) converts cortisone to cortisol for intracrine action (26). Among other regulatory mechanisms of enzyme activity (27), GH inhibits 11␤-HSD-1 activity and gene expression, while GH deficiency is associated with enhanced enzyme activity (28 -31).The working hypotheses of this study were that SSGA children will have increased basal and GC-stimulated 11␤-HSD-1 activity and that these will be inhibited by GH treatment. Toward these hypotheses, we studied in vivo 11␤-HSD-1 activity, as measured by the ratio...

show abstract

Modulation of 11β-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers

Cited by 72 publications

References 77 publications

Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

Regulation of glucocorticoid sensitivity in thymocytes from burn-injured mice

Type 2 diabetes and metabolic syndrome are associated with increased expression of 11β-hydroxysteroid dehydrogenase 1 in obese subjects

11β–Hydroxysteroid Dehydrogenase Type 1 Activity in Short Small-For-GA Children and in Response to GH Therapy

Contact Info

Product

Resources

About