Regeneration Of Glucocorticoids Research Articles

The dual role of glucocorticoid regeneration in inflammation at parturition.

Fetal membrane inflammation is an integral event of parturition. However, excessive pro-inflammatory cytokines can impose threats to the fetus. Coincidentally, the fetal membranes express abundant 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which generates biologically active cortisol to promote labor through induction of prostaglandin synthesis. Given the well-recognized anti-inflammatory actions of glucocorticoids, we hypothesized that cortisol regenerated in the fetal membranes might be engaged in restraining fetus-hazardous pro-inflammatory cytokine production for the safety of the fetus, while reserving pro-labor effect on prostaglandin synthesis to ensure safe delivery of the fetus. The hypothesis was examined in human amnion tissue and cultured primary human amnion fibroblasts as well as a mouse model. 11β-HSD1 was significantly increased in the human amnion in infection-induced preterm birth. Studies in human amnion fibroblasts showed that lipopolysaccharide (LPS) induced 11β-HSD1 expression synergistically with cortisol. Cortisol completely blocked NF-κB-mediated pro-inflammatory cytokine expression by LPS, but STAT3-mediated cyclooxygenase 2 expression, a crucial prostaglandin synthetic enzyme, remained. Further studies in pregnant mice showed that corticosterone did not delay LPS-induced preterm birth, but alleviated LPS-induced fetal organ damages, along with increased 11β-HSD1, cyclooxygenase 2, and decreased pro-inflammatory cytokine in the fetal membranes. There is a feed-forward cortisol regeneration in the fetal membranes in infection, and cortisol regenerated restrains pro-inflammatory cytokine expression, while reserves pro-labor effect on prostaglandin synthesis. This dual role of cortisol regeneration can prevent excessive pro-inflammatory cytokine production, while ensure in-time delivery for the safety of the fetus.

Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

Contribution of local regeneration of glucocorticoids to tissue steroid pools.

11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

Tissue-specific expression of 11β-HSD and its effects on plasma corticosterone during the stress response.

The hypothalamic-pituitary-adrenal (HPA) axis is under complex regulatory control at multiple levels. Enzymatic regulation plays an important role in both circulating levels of glucocorticoids and target tissue exposure. Three key enzyme pathways are responsible for the immediate control of glucocorticoids. De novo synthesis of glucocorticoid from cholesterol involves a multistep enzymatic cascade. This cascade terminates with 11β-hydroxylase, responsible for the final conversion of 11-deoxy precursors into active glucocorticoids. Additionally, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls regeneration of glucocorticoids from inactive metabolites, providing a secondary source of active glucocorticoids. Localized inactivation of glucocorticoids is under the control of Type 2 11β-HSD (11β-HSD2). The function of these enzymes is largely unexplored in wild species, particularly songbirds. Here, we investigated the contribution of both clearance and generation of glucocorticoids to regulation of the hormonal stress response via the use of pharmacological antagonists. Additionally, we mapped 11β-HSD gene expression. We found 11β-HSD1 primarily in liver, kidney and adrenal glands, although it was detectable across all tissue types. 11β-HSD2 was predominately expressed in the adrenal glands and kidney with moderate gonadal and liver expression. Inhibition of glucocorticoid generation by metyrapone was found to decrease levels peripherally, while both peripheral and central administration of the 11β-HSD2 inhibitor DETC resulted in elevated concentrations of corticosterone. These data suggest that during the stress response, peripheral antagonism of the 11β-HSD system has a greater impact on circulating glucocorticoid levels than central control. Further studies should aim to elucidate the respective roles of the 11β-HSD and 11β-hydroxylase enzymes.

Social defeat stimulates local glucocorticoid regeneration in lymphoid organs.

Stress is an important risk factors for human diseases. It activates the hypothalamic–pituitary–adrenal (HPA) axis and increases plasma glucocorticoids, which are powerful regulators of immune system. The response of the target cells to glucocorticoids depends not only on the plasma concentrations of cortisol and corticosterone but also on their local metabolism. This metabolism is catalyzed by 11β-hydroxysteroid dehydrogenases type 1 and 2, which interconvert glucocorticoid hormones cortisol and corticosterone and their 11-oxo metabolites cortisone and 11-dehydrocorticosterone. The goal of this study was to determine whether stress modulates glucocorticoid metabolism within lymphoid organs – the structures where immune cells undergo development and activation. Using the resident-intruder paradigm, we studied the effect of social stress on glucocorticoid metabolism in primary and secondary lymphoid organs of Fisher 344 (F344) and Lewis (LEW) rats, which exhibit marked differences in their HPA axis response to social stressors and inflammation. We show that repeated social defeat increased the regeneration of corticosterone from 11-dehydrocorticosterone in the thymus, spleen and mesenteric lymphatic nodes (MLN). Compared with the F344 strain, LEW rats showed higher corticosterone regeneration in splenocytes of unstressed rats and in thymic and MLN mobile cells after stress but corticosterone regeneration in the stroma of all lymphoid organs was similar in both strains. Inactivation of corticosterone to 11-dehydrocorticosterone was found only in the stroma of lymphoid organs but not in mobile lymphoid cells and was not upregulated by stress. Together, our findings demonstrate the tissue- and strain-dependent regeneration of glucocorticoids following social stress.

Androgens modulate glucocorticoid receptor activity in adipose tissue and liver.

Glucocorticoid signaling is context-dependent, and in certain scenarios glucocorticoid receptors (GR) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk between glucocorticoids and androgens in metabolic tissues including white adipose tissue, liver and brown adipose tissue. Thereto we exposed male C57BL/6J mice to elevated levels of corticosterone in combination with an androgen receptor (AR) agonist or an AR antagonist. Systemic and local glucocorticoid levels were determined by mass spectrometry, tissue expression of glucocorticoid-responsive genes and protein was measured by RT-qPCR and Western blot, respectively. To evaluate crosstalk in vitro, cultured white and brown adipocytes were exposed to a combination of corticosterone and an androgen agonist. We found that AR agonism potentiated transcriptional response to GR in vitro in white and brown adipocytes and in vivo in white and brown adipose tissue. Conversely, AR antagonism substantially attenuated glucocorticoid signaling in white adipose tissue and liver. In white adipose tissue this effect could partially be attributed to decreased 11B-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid regeneration upon AR antagonism. In liver, attenuated GR activity was independent of active glucocorticoid ligand levels. We conclude that androgen signaling modulates GR transcriptional output in a tissue-specific manner.

Analgesic effects of ASP3662, a novel 11β-hydroxysteroid dehydrogenase 1 inhibitor, in rat models of neuropathic and dysfunctional pain.

Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11β-HSD1 inhibitor, on neuropathic and dysfunctional pain. The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. ASP3662 inhibited human, mouse and rat 11β-HSD1 but not human 11β-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11β-HSD1. The effects of ASP3662 suggest that selective inhibition of 11β-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.

Midlife stress alters memory and mood-related behaviors in old age: Role of locally activated glucocorticoids

Chronic exposure to stress during midlife associates with subsequent age-related cognitive decline and may increase the vulnerability to develop psychiatric conditions. Increased hypothalamic-pituitary-adrenal (HPA) axis activity has been implicated in pathogenesis though any causative role for glucocorticoids is unestablished. This study investigated the contribution of local glucocorticoid regeneration by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), in persisting midlife stress-induced behavioral effects in mice. Middle-aged (10 months old) 11β-HSD1-deficient mice and wild-type congenic controls were randomly assigned to 28 days of chronic unpredictable stress or left undisturbed (non-stressed). All mice underwent behavioral testing at the end of the stress/non-stress period and again 6–7 months later. Chronic stress impaired spatial memory in middle-aged wild-type mice. The effects, involving a wide spectrum of behavioral modalities, persisted for 6–7 months after cessation of stress into early senescence. Enduring effects after midlife stress included impaired spatial memory, enhanced contextual fear memory, impaired fear extinction, heightened anxiety, depressive-like behavior, as well as reduced hippocampal glucocorticoid receptor mRNA expression. In contrast, 11β-HSD1 deficient mice resisted both immediate and enduring effects of chronic stress, despite similar stress-induced increases in systemic glucocorticoid activity during midlife stress. In conclusion, chronic stress in midlife exerts persisting effects leading to cognitive and affective dysfunction in old age via mechanisms that depend, at least in part, on brain glucocorticoids generated locally by 11β-HSD1. This finding supports selective 11β-HSD1 inhibition as a novel therapeutic target to ameliorate the long-term consequences of stress-related psychiatric disorders in midlife.

11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI.

We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1−/−) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in ‘host’ myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the myocardium of Hsd11b1−/− mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1−/− mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5. These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

Forebrain-Specific Transgene Rescue of 11β-HSD1 Associates with Impaired Spatial Memory and Reduced Hippocampal Brain-Derived Neurotrophic Factor mRNA Levels in Aged 11β-HSD1 Deficient Mice.

Mice lacking the intracellular glucocorticoid‐regenerating enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) are protected from age‐related spatial memory deficits. 11β‐HSD1 is expressed predominantly in the brain, liver and adipose tissue. Reduced glucocorticoid levels in the brain in the absence of 11β‐HSD1 may underlie the improved memory in aged 11β‐HSD1 deficient mice. However, the improved glucose tolerance, insulin sensitisation and cardioprotective lipid profile associated with reduced peripheral glucocorticoid regeneration may potentially contribute to the cognitive phenotype of aged 11β‐HSD1 deficient mice. In the present study, transgenic mice with forebrain‐specific overexpression of 11β‐HSD1 (Tg) were intercrossed with global 11β‐HSD1 knockout mice (HSD1KO) to examine the influence of forebrain and peripheral 11β‐HSD1 activity on spatial memory in aged mice. Transgene‐mediated delivery of 11β‐HSD1 to the hippocampus and cortex of aged HSD1KO mice reversed the improved spatial memory retention in the Y‐maze but not spatial learning in the watermaze. Brain‐derived neurotrophic factor (BDNF) mRNA levels in the hippocampus of aged HSD1KO mice were increased compared to aged wild‐type mice. Rescue of forebrain 11β‐HSD1 reduced BDNF mRNA in aged HSD1KO mice to levels comparable to aged wild‐type mice. These findings indicate that 11β‐HSD1 regenerated glucocorticoids in the forebrain and decreased levels of BDNF mRNA in the hippocampus play a role in spatial memory deficits in aged wild‐type mice, although 11β‐HSD1 activity in peripheral tissues may also contribute to spatial learning impairments in aged mice.

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium.

Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

Nicotinamide riboside and cellular NAD+ redox state influence 11[beta]-HSD1 mediated glucocorticoid regeneration in skeletal muscle cells

Nicotinamide riboside and cellular NAD+ redox state influence 11[beta]-HSD1 mediated glucocorticoid regeneration in skeletal muscle cells

Potential role of renal mineralocorticoid receptor increasing the blood pressure sensitivity in female mice exposed to early life stress (ELS)

Epidemiological studies have shown that exposure to ELS increases the number of risk factors to develop cardiovascular and metabolic disease later in life. Previously, we have shown that C57BL/6 mice exposed to maternal separation (MatSep), a model of ELS, display exaggerated diet‐induced obesity. However, only female MatSep mice show increased visceral fat and glucose intolerance compared to male MatSep mice. In addition, we have reported increased local glucocorticoid regeneration in liver and adipose tissue as a potential mechanism of ELS‐induced obesity. The aim of this study was to investigate the impact of MatSep in combination with a high fat diet (HFD) on blood pressure and renal gene expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and 11 β‐hydroxysteroid dehydrogenase types 1 and 2. MatSep was performed in C57BL/6 mice pups by daily separation from the dam during the first two weeks of life. Non‐disturbed litters were used as controls. Upon weaning, mice were fed a HFD (60% kcal from fat) for 16 weeks. Female mice were implanted with radiotelemetry at week 14 (DSI, n=4–5). Whole kidney tissue from female mice was collected and snap frozen for gene expression determination using RT‐PCR (n=6–8). Mean arterial pressure (24hr average) was elevated in female MatSep mice compared to control (133.1±0.1 vs. 122.8±0.7 mmHg, p<0.05). Pulse pressure was increased in MatSep mice as well (35.1±0.1 vs. 31.4±0.4 mmHg, p<0.05). No differences were observed in HR (622.2±21.6 vs. 638.1±28.5 bpm, p<0.05); however, spontaneous baroreflex sensitivity was reduced in female mice exposed to MatSep (1.67±0.18 vs. 2.52±0.24 msec/mmHg, p<0.05). Renal expression levels of 11βHSD1 were similar in female MatSep and control mice fed a HFD. Yet, 11βHSD2 mRNA expression was attenuated in female MatSep mice compared to control mice (0.6±0.1 vs. 1.0±0.1 fold, p<0.05). GR expression was similar between groups but MR expression was reduced in MatSep mice vs. control (0.5±0.1 vs. 1.0±0.1 fold, respectively, p<0.05). Additional experiments revealed that MatSep had no effect on renal 11βHSD1 or 11βHSD2 mRNA expression in male mice. Furthermore, no differences in gene expression were observed between MatSep and control groups when the mice were fed a low fat diet. Interestingly, estrogen receptor β (ERβ) mRNA expression in the kidney was significantly upregulated in obese female MatSep mice (3.8±0.3 vs. 1.1±0.2 fold, respectively, p<0.05), with no differences in ERα expression. Since the analysis of the 11βHSD2 promoter revealed 4 estrogen response elements ~50,000 bp near to its start point, further investigation in the control of this enzyme by estradiol will be conducted. Taken together, these data suggest that in response to a second hit such as HFD, MatSep may induce MR overstimulation leading to increases in blood pressure sensitivity in female mice.Support or Funding InformationNIH R00 HL111354; COBRE P20 GM103527‐06

Local glucocorticoid synthesis and regeneration in lymphoid organs: Neonatal and adult mice

Glucocorticoids are synthesized in the adrenal glands and circulate through the blood to coordinate organismal physiology. In early life, elevated glucocorticoids suppress growth and neural development, and altricial neonates avoid these deleterious effects by undergoing a stress hyporesponsive period during which circulating glucocorticoids are low. However, elevated glucocorticoids may be needed in other tissues, such as the thymus, for their critical role in production of immunocompetent T cells. Here, we show that lymphoid organs increase their local glucocorticoid levels via glucocorticoid production, and that production increases with age. Murine lymphoid organs (thymus, bone marrow, spleen) produced corticosterone in vitro, and this production was blocked by metyrapone, which inhibits both CYP11B1 synthesis of corticosterone from precursors (deoxycorticosterone) and 11beta-HSD1 regeneration of corticosterone from metabolites (dehydrocorticosterone). Gene expression and enzyme activity of 11beta-HSD1 were much higher than expression and activity of CYP11B1, which were extremely low or nondetectable. Adults showed higher 11beta-HSD1 expression and activity than neonates. These findings show that lymphoid organs produce glucocorticoids via regeneration, and that regeneration increases with age. Furthermore, regeneration occurs not only in the thymus, where glucocorticoids are necessary for T cell development, but also in bone marrow and spleen, the sites of B cell development. As developing B cells have high levels of glucocorticoid receptors, locally-produced glucocorticoids likely play a critical role in both T and B cell development.

Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease.

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia.

β-Cell-Specific Glucocorticoid Reactivation Attenuates Inflammatory β-Cell Destruction.

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1tg/+ mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1tg/+ mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1tg/+ mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1tg/+ islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.

Genetic variants of the HSD11B1 gene promoter may be protective against polycystic ovary syndrome.

The HSD11B1 gene encodes the type 1 isoform of the 11-β-hydroxysteroid dehydrogenase that is responsible for the regeneration of glucocorticoids from hormonally-inactive metabolites into active forms in a tissue-specific manner. Altered activity of the enzyme, and certain genetic variants of the HSD11B1 gene, has been associated with various metabolic morbidities. In this study, our aim was to systematically test the potential role of the HSD11B1's single nucleotide polymorphisms (SNPs) in polycystic ovary syndrome (PCOS). Nine HSD11B1 SNPs were selected and genotyped using Taqman SNP assays on real-time PCR in a group of PCOS patients (n = 58) and in age-matched healthy controls (n = 64). Genotype-phenotype correlations were determined and haplotype analysis was performed. An in silico prediction for potential transcription factor binding sites was also performed. Of the 5 promoter SNPs, 3 (rs760951; rs4844880; rs3753519) were less frequent in the PCOS group compared to healthy controls. SNPs rs4844880 and rs3753519 were in a complete linkage and the mutant haplotype (AA) was less frequent in the PCOS group. No association between HSD11B1 variants and clinical, pathological findings was observed in patients, but in healthy women the rs4844880 and the AA haplotype were associated with higher levels of homeostasis model assessment of beta cell function. The polymorphic form of the rs4844880 was predicted to bind Pbx-1. Promoter SNPs of the HSD11B1 gene might exert a potential genetic protective role against the development of PCOS, possibly via their beneficial effect on carbohydrate homeostasis due to facilitation of insulin efflux from pancreatic beta-cells.

216 Immediate Pharmacological Inhibition of Local Glucocorticoid Generation increases Angiogenesis and Improves Cardiac Funcion after Myocardial Infarction

Mice lacking the glucocorticoid regenerating enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), responsible for local regeneration of corticosterone, have increased peri-infarct angiogenesis (Small et al ., 2005) and improved cardiac...

Associations between maternal level of education and occupational status with placental glucocorticoid regeneration and sensitivity

Low socio-economic status (SES) is associated with increased disease risk in the involved and the next generation. The effects of low maternal SES on the offspring may be initiated prenatally. We hypothesized that fetoplacental glucocorticoid exposure might mediate the links. We examined associations between maternal level of education and occupational status (used as indices of SES) and placental expression of genes involved in glucocorticoid exposure and transfer between the mother and foetus. Placental biopsies were obtained from 67 healthy women (age 32.2 ± 5.3 years) with singleton, term pregnancies without obstetric complications who participated in a prospective Prediction and Prevention of Preeclampsia (PREDO) study. Level of education was self-reported, and occupational status was extracted from hospital records. Relative glucocorticoid receptor (GR; NR3C1), mineralocorticoid receptor (MR; NR3C2) and 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) and 2 (HSD11B2) mRNA levels were quantified by real-time PCR. Placental GR and HSD11B1 expression increased with decreasing maternal education (unadjusted P-values for linear trend = 0.04 and 0.02 and adjusted P-values = 0.06 and 0.09, respectively). Mothers with primary/secondary education had 52.9% (95% CI, 6.2-99.6, P = 0.03, adjusted P = 0.05) and 79.6% (95% CI, 6.5-153.6, P = 0.03, adjusted P = 0.09) higher GR and HSD11B1 mRNA levels compared with mothers with tertiary education. There were no other significant associations. Lower maternal level of education is associated with increased placental GR and HSD11B1 gene expression. This combination may regenerate active glucocorticoids in placenta and increase placental sensitivity to glucocorticoids, potentially leading to greater placental and foetal glucocorticoid exposure.

Dietary fructose-related adiposity and glucocorticoid receptor function in visceral adipose tissue of female rats

Excessive fructose intake coincides with the growing rate of obesity and metabolic syndrome, with women being more prone to these disorders than men. Findings that detrimental effects of fructose might be mediated by glucocorticoid regeneration in adipose tissue only indirectly implicated glucocorticoid receptor (GR) in the phenomenon. The aim of the present study was to elucidate whether fructose overconsumption induces derangements in GR expression and function that might be associated with fructose-induced adiposity in females. We examined effects of fructose-enriched diet on GR expression and function in visceral adipose tissue of female rats. Additionally, we analyzed the expression of genes involved in glucocorticoid prereceptor metabolism [11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase], lipolysis (hormone-sensitive lipase) and lipogenesis (sterol regulatory element binding protein 1 and peroxisomal proliferator-activated receptor γ). Fructose-fed rats had elevated energy intake that resulted in visceral adiposity, as indicated by increased visceral adipose tissue mass and its share in the whole-body weight. GR hormone binding capacity and affinity, as well as the expression of GR gene at both mRNA and protein levels were reduced in visceral adipose tissue of the rats on fructose diet. The glucocorticoid prereceptor metabolism was stimulated, as evidenced by elevated tissue corticosterone, while the key regulators of lipolysis and lipogenesis remained unaffected by fructose diet. The results suggest that the 11βHSD1-mediated elevation of intracellular corticosterone may induce GR downregulation, which may be associated with failure of GR to stimulate lipolysis in fructose-fed female rats.