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Showing papers on "Adrenal cortex published in 2013"


Journal ArticleDOI
TL;DR: The current study indicates that the adrenal gland secretes primarily 3 weak androgens, namely DHEA, 11OHA, and A4, which are found to be potent androgen receptor agonists when tested with an androgen-responsive cell reporter model.
Abstract: Context: A broad analysis of adrenal gland-derived 19-carbon (C19) steroids has not been reported. This is the first study that uses liquid chromatography–tandem mass spectrometry to quantify 9 C19 steroids (androgens and their precursors), estrone, and estradiol in the adrenal vein (AV) of women, before and after ACTH stimulation. Objective: The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion. Design: This was a retrospective study. Patients: Seven women, aged 50.4 ± 5.4 years, with suspected diagnosis of an adrenal aldosterone-producing adenoma were included in the study. Methods: AV and iliac serum samples were collected before and after administration of ACTH (15 minutes). AV samples were analyzed using for concentrations of 9 unconjugated C19 steroids, estrone, and estradiol. Dehydroepiandrosterone sulfate (DHEA-S) was quantified by radioimmunoassay. Results: AV levels of DHEA-S were the highest among the steroids measured. The most abunda...

187 citations


Journal ArticleDOI
TL;DR: It is demonstrated that adrenocortical zonation and regeneration result from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues.

142 citations


Journal ArticleDOI
TL;DR: It is demonstrated that Dicer-dependent miRNA, including miR-24, can post-transcriptionally regulate expression of the CYP 11B1 and CYP11B2 genes, which produce the enzymes responsible for the final stages of cortisol and aldosterone biosynthesis.
Abstract: Dysregulation of aldosterone or cortisol production can predispose to hypertension, as seen in aldosterone-producing adenoma, a form of primary aldosteronism. We investigated the role of microRNA (miRNA) in their production, with particular emphasis on the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes, which produce the enzymes responsible for the final stages of cortisol and aldosterone biosynthesis, respectively. Knockdown of Dicer1, a key enzyme in miRNA maturation, significantly altered CYP11B1 and CYP11B2 expression in a human adrenocortical cell line. Screening of nondiseased human adrenal and aldosterone-producing adenoma samples yielded reproducible but distinctive miRNA expression signatures for each tissue type, with levels of certain miRNA, including microRNA-24 (miR-24), differing significantly between the 2. Bioinformatic analysis identified putative binding sites for several miRNA, including miR-24, in the 3' untranslated region of CYP11B1 and CYP11B2 mRNAs. In vitro manipulation of miR-24 confirmed its ability to modulate CYP11B1 and CYP11B2 expression, as well as cortisol and aldosterone production. This study demonstrates that Dicer-dependent miRNA, including miR-24, can post-transcriptionally regulate expression of the CYP11B1 and CYP11B2 genes. Normal adrenal tissue and aldosterone-producing adenoma differ significantly and reproducibly in their miRNA expression profiles, with miR-24 significantly downregulated in the latter. Adrenal miRNA may, therefore, be a novel and valid target for the therapeutic manipulation of corticosteroid biosynthesis.

77 citations


Journal ArticleDOI
TL;DR: It is demonstrated that subsets of capsular cells are descendants of fetal adrenocortical cells that once expressed Nr5a1, and the mechanism by which two populations of fetal cells participate in the establishment of the homeostatic capsular progenitor cell niche of the adult cortex is uncovered.
Abstract: The lineage relationships of fetal adrenal cells and adrenal capsular cells to the differentiated adrenal cortex are not fully understood. Existing data support a role for each cell type as a progenitor for cells of the adult cortex. This report reveals that subsets of capsular cells are descendants of fetal adrenocortical cells that once expressed Nr5a1. These fetal adrenocortical cell descendants within the adrenal capsule express Gli1, a known marker of progenitors of steroidogenic adrenal cells. The capsule is also populated by cells that express Tcf21, a known inhibitor of Nr5a1 gene expression. We demonstrate that Tcf21-expressing cells give rise to Nr5a1-expressing cells but only before capsular formation. After the capsule has formed, capsular Tcf21-expressing cells give rise only to non-steroidogenic stromal adrenocortical cells, which also express collagen 1a1, desmin and platelet-derived growth factor (alpha polypeptide) but not Nr5a1. These observations integrate prior observations that define two separate origins of adult adrenocortical steroidogenic cells (fetal adrenal cortex and/or the adrenal capsule). Thus, these observations predict a unique temporal and/or spatial role of adult cortical cells that arise directly from either fetal cortical cells or from fetal cortex-derived capsular cells. Last, the data uncover the mechanism by which two populations of fetal cells (fetal cortex derived Gli1-expressing cells and mesenchymal Tcf21-expressing mesenchymal cells) participate in the establishment of the homeostatic capsular progenitor cell niche of the adult cortex.

74 citations


Journal ArticleDOI
TL;DR: The results suggest that immune cells, rather than adrenal cells, are major regulators of the systemic and intra-adrenal inflammatory response to LPS, and an important role of immune cellrather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.
Abstract: Inflammation-related dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune–adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune–adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1Cre+-MyD88fl/fl mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

68 citations


Book ChapterDOI
TL;DR: The transcriptional networks and signaling pathways involved in development and maintenance of the gland and in its pathology are discussed in the light of the wealth of physiological information gathered in studies of human and rodent adrenal development and function.
Abstract: The adrenal gland controls a plethora of crucial physiological functions, and dysfunction is associated with severe morbidity. Because of the vital importance of appropriate adrenal function, the development and function of the gland have been intensively studied, and these investigations have revealed fascinating developmental origins and a remarkable remodeling and regenerative capacity in the adult. This chapter, focusing on the adrenal cortex, will describe our current understanding of the development and maintenance of the adrenal gland, which has been advanced over recent years by the use of sophisticated genetic models in the study of both normal function and disease. This work has shed light on the transcriptional networks and signaling pathways involved in development and maintenance of the gland and in its pathology; these are discussed in the light of the wealth of physiological information gathered in studies of human and rodent adrenal development and function.

65 citations


Journal ArticleDOI
TL;DR: The nature, regulation and known physiological roles of extra-adrenal GC synthesis in the thymus are summarized, in which GC production by both developing thymocytes and epithelial cells has a role in the maintenance of proper immunological function.

57 citations


Journal ArticleDOI
TL;DR: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits.
Abstract: Primary adrenal cortical insufficiency, known as adrenal insufficiency (AI) or Addisons disease, is rare with a prevalence of approximately 100/1 million/year (1, 2). The incidence of primary AI is approximately 5/1 million/year and has been rising in recent years (1– 3) (e1). Autoimmune-mediated adrenalitis accounts for over 80% of cases in industrialized countries (2). Most patients are young to middle-aged, with more females than males affected. However, this disease affects patients of all ages and in patients under 30 years there is no sex disparity (e2). Irreversible damage to the adrenal cortex leads to insufficient production of glucocorticoids, mineralocorticoids, and androgens. Over the course of their illness, nearly 60% of patients with autoimmune-mediated AI will be diagnosed with further autoimmune diseases as part of a polyglandular autoimmune syndrome (table 1). Table 1 Causes of adrenal cortical insufficiency The secondary form of adrenal cortical insufficiency is caused by a dysfunction at the level of the pituitary (incidence: 20/1 million/year; prevalence 400/1 million). The main causes are the displacement of corticotropic cells by pituitary macroadenomas or traumatic injury (table 1) (4, e3). A deficiency of adrenocorticotropic hormone (ACTH) blocks the stimulation of cortisol production. The adrenal cortex atrophies, and cortisol secretion dwindles. Due to the variety of causes, there is no peak incidence according to age or sex. By far, the most common cause of adrenal cortical insufficiency is pharmacotherapy with synthetic glucocorticoids (0.5 to 2% of the population) (5). Such therapy can lead to suppression of the hypothalamic-pituitary-adrenal axis (HPA axis) with atrophy of the corticotropic cells of the pituitary gland and the adrenal cortex (tertiary adrenal cortical insufficiency). High-dose steroid therapy (20–30 mg prednisolone equivalent) can lead to suppression of the regulatory cycle after just a few days (6, e4). In general, the risk of adrenal cortical insufficiency increases with the dose and duration of therapy. Depot preparations and evening administration of higher glucocorticoid doses also increase the risk. Adrenocorticosuppression is difficult to predict in individual cases, hence all patients, even those receiving low-dose glucocorticoid therapy, must be generally considered at risk for the development of adrenal cortical insufficiency (7). The current article aims to provide new insight into the management of patients with adrenal cortical insufficiency. A selective literature search of Medline was performed with special focus on recent studies published since the year 2000 (search words: “adrenal insufficiency“ or „Addisons disease“ or „hypopituitarism”). The search yielded 451 articles, and relevant articles were selected.

50 citations


Journal ArticleDOI
TL;DR: In vitro data in AAAS-knockdown adrenal and neuronal cells not only corroborates previous studies implicating oxidative stress in this disorder but also provides further insights into the pathogenic mechanisms in triple A syndrome.
Abstract: Triple A syndrome is a rare, autosomal recessive cause of adrenal failure. Additional features include alacrima, achalasia of the esophageal cardia, and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN), of unknown function. Triple A syndrome patient dermal fibroblasts appear to be more sensitive to oxidative stress than wild-type fibroblasts. To provide an adrenal and neuronal-specific disease model, we established AAAS-gene knockdown in H295R human adrenocortical tumor cells and SH-SY5Y human neuroblastoma cells by lentiviral short hairpin RNA transduction. AAAS-knockdown significantly reduced cell viability in H295R cells. This effect was exacerbated by hydrogen peroxide treatment and improved by application of the antioxidant N-acetylcysteine. An imbalance in redox homeostasis after AAAS knockdown was further suggested in the H295R cells by a decrease in the ratio of reduced to oxidiz...

49 citations


Journal ArticleDOI
TL;DR: Evidence is provided that inflammation and metabolic changes reduce the concentration of circulating plasma cortisol during an acute stress, and the acute phase response in dairy cows should be taken into account to interpret the results obtained from stimulation tests of the adrenal cortex.

44 citations


Journal ArticleDOI
TL;DR: Genetic proof is offered that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells into gonadal-like cells, and limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy.
Abstract: Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.

Journal ArticleDOI
04 Dec 2013-PLOS ONE
TL;DR: Investigating cell proliferation, movement and differentiation in the adult mouse adrenal cortex using different 5-bromo-2'-deoxyuridine (BrdU) labelling regimens and immunostaining for phenotypic steroidogenic cell markers revealed some outer cortical BrdU-positive cells were induced to proliferate following acute adrenocorticotropic hormone (ACTH) treatment.
Abstract: Appropriate maintenance and regeneration of adult endocrine organs is important in both normal physiology and disease. We investigated cell proliferation, movement and differentiation in the adult mouse adrenal cortex, using different 5-bromo-2'-deoxyuridine (BrdU) labelling regimens and immunostaining for phenotypic steroidogenic cell markers. Pulse-labelling showed that cell division was largely confined to the outer cortex, with most cells moving inwards towards the medulla at around 13-20 µm per day, though a distinct labelled cell population remained in the outer 10% of the cortex. Pulse-chase-labelling coupled with phenotypic immunostaining showed that, unlike cells in the inner cortex, most BrdU-positive outer cortical cells did not express steroidogenic markers, while co-staining for BrdU and Ki67 revealed that some outer cortical BrdU-positive cells were induced to proliferate following acute adrenocorticotropic hormone (ACTH) treatment. Extended pulse-chase-labelling identified cells in the outer cortex which retained BrdU label for up to 18-23 weeks. Together, these observations are consistent with the location of both slow-cycling stem/progenitor and transiently amplifying cell populations in the outer cortex. Understanding the relationships between these distinct adrenocortical cell populations will be crucial to clarify mechanisms underpinning adrenocortical maintenance and long-term adaptation to pathophysiological states.

Journal ArticleDOI
TL;DR: Results indicate that mitotane markedly inhibited expression of genes involved in steroidogenesis, secretion of cortisol and DHEAS, and resulted in decreased mRNA levels of two cytochromes P450 (CYP11A1 and CYP17A1) and MYC (encoding cMyc).
Abstract: Mitotane, also known as o,p'‑DDD or (RS)‑1‑chl-oro‑2‑[2,2‑dichloro‑1‑(4‑chlorophenyl)‑ethyl]‑benzene, is an adrenal cortex-specific cytotoxic drug used in the therapy of adrenocortical carcinoma (ACC). The drug also inhibits steroidogenesis, however, the mechanisms of its anticancer and antisteroidogenic effects remain unknown. At present, data on the impact of mitotane on cell viability and the regulation of genes encoding proteins associated with steroids synthesis in the adrenal cortex, including cortisol and dehydroepiandrosterone sulfate (DHEAS), are limited and contradictory. In the present study, the effect of 24‑h mitotane treatment on viability of the ACC cell line, NCI‑H295R, was analyzed, identifying a decrease in cell viability and an increase in caspase‑3 and ‑7 activities. Mitotane treatment also led to decreased cortisol and DHEAS concentration in the culture media. Concomitantly, mitotane resulted in decreased mRNA levels of two cytochromes P450 (CYP11A1 and CYP17A1), mRNAs encoding proteins involved in the synthesis of cortisol and DHEAS. Mitotane did not affect mRNA levels of cyclin dependent kinase inhibitor 1A (encoding p21) and MYC (encoding cMyc). cMyc and p21 are key transcription factors associated with cell cycle regulation. However, mitotane inhibited expression of transforming growth factor β1 gene, encoding a potent inhibitor of cell proliferation and steroidogenesis. PRKAR1A, a protein kinase A regulatory subunit, is involved in the activation of steroidogenesis. PRKAR1A mRNA levels were reduced following 24‑h treatment with mitotane. Results indicate that mitotane markedly inhibited expression of genes involved in steroidogenesis, secretion of cortisol and DHEAS. Reduced expression of TGFB1 cannot account fully for the effect of mitotane on CYP11A1 and CYP17A1. We hypothesized that reduced viability of NCI‑H295R cells in the presence of mitotane may be a result of apoptosis triggered by increased caspase‑3 and ‑7 activities. Since p21 and cMyc mRNA levels were stable in the presence of mitotane, the mechanism by which caspase‑3 and ‑7 are induced remains unknown.

Journal ArticleDOI
TL;DR: There was no correlation between KCNJ5 mutation status and the morphological measures of adrenal cortex remodeling, including nodulation, vascularization and expression of CYP11B2, and the cell composition of APA was not significantly different between groups.

Journal ArticleDOI
TL;DR: The biology and treatment of Pheochromocytomas, paragangliomas, and medullary thyroid carcinomas, which originate in cells that share a common neuroectodermal origin, are reviewed.

Journal ArticleDOI
01 Jan 2013-Stress
TL;DR: Results support the notion of altered HPA axis regulation in chronically work-stressed teachers, with differential patterns of hyper- and hyporeactivity depending on individual stress condition and the tested functional level of the HPAaxis.
Abstract: Evidence for a detrimental impact of chronic work stress on health has accumulated in epidemiological research. Recent studies indicate altered hypothalamus-pituitary-adrenal (HPA) axis regulation as a possible biological pathway underlying the link between stress and disease. However, the direction of dysregulation remains unclear, with reported HPA hyper- or hyporeactivity. To disentangle potential effects on different functional levels in the HPA axis, we examined responses using two pharmacological stimulation tests in 53 healthy teachers (31 females, 22 males; mean age: 49.3 years; age range: 30-64 years): a low-dose adrenocorticotrophic hormone (ACTH(1-24), Synacthen) test was used to assess adrenal cortex sensitivity and the combined dexamethasone-corticotropin releasing hormone (DEX-CRH) test to examine pituitary and adrenal cortex reactivity. Blood and saliva samples were collected at - 1,+15,+30,+45,+60,+90,+120 min. Emotional exhaustion (EE), the core dimension of burnout, was measured with the Maslach Burnout Inventory. Overcommitment (OC) was assessed according to Siegrist's effort-reward-imbalance model. We found a significant association between EE and higher plasma cortisol profiles after Synacthen (p = 0.045). By contrast, OC was significantly associated with attenuated ACTH (p = 0.045), plasma cortisol (p = 0.005), and salivary cortisol (p = 0.023) concentrations following DEX-CRH. Results support the notion of altered HPA axis regulation in chronically work-stressed teachers, with differential patterns of hyper- and hyporeactivity depending on individual stress condition and the tested functional level of the HPA axis.

Journal ArticleDOI
TL;DR: The adrenal glands from fgfr2 IIIb knock-out mice are hypoplastic and FGF1 is proposed as the ligand for FGFR2IIIb in the adrenal cortex, and Dlk1, rather than Shh, signalling is affected in the Adrenal cortex.

Journal ArticleDOI
27 May 2013-PLOS ONE
TL;DR: Data suggest the existence of a negative feedback on interrenal sbMC2R expression imposed by local or systemic glucocorticoids, and ACTH-induced MC2R activation stimulates hepatic lipolysis, suggesting that ACTH may mediate stress-induced effects upstream of cortisol release.
Abstract: The activation of melanocortin 2 receptor (MC2R) by ACTH mediates the signaling cascade leading to steroid synthesis in the interrenal tissue (analogous to the adrenal cortex in mammals) of fish. However, little is known about the functional regulation of this receptor in fish. In this work described, we cloned sea bass MC2R from a liver cDNA. SbMC2R requires the melanocortin 2 receptor accessory protein (MRAP) for its functional expression. Dietary cortisol but not long-term stress protocols downregulated interrenal sbMC2R expression. Data suggest the existence of a negative feedback on interrenal sbMC2R expression imposed by local or systemic glucocorticoids. This feedback could be involved in long-term stress adaptation by regulating interrenal sensitivity to ACTH. ACTH-induced MC2R activation stimulates hepatic lipolysis, suggesting that ACTH may mediate stress-induced effects upstream of cortisol release.

Journal ArticleDOI
TL;DR: It is suggested that CRS promotes endocrine disruption involving decreased ACTH and sensitized CORT responses to acute restraint as compared to CTRL conditions and may be associated with increased function and expression of 5-HT₇ receptors as well as 5- HT turnover in AG.

Journal ArticleDOI
TL;DR: It is demonstrated that Shh and Dlk1 are coexpressed in the outer undifferentiated zone of the male rat adrenal and that DlK1 signals to the adrenal capsule, activating glioma-associated oncogene homolog 1 transcription in a β1 integrin- and Erk1/2-dependent fashion.
Abstract: The development and maintenance of the zones of the adrenal cortex and their steroidal output are extremely important in the control of gluconeogenesis, the stress response, and blood volume. Sonic Hedgehog (Shh) is expressed in the adrenal cortex and signals to capsular cells, which can respond by migrating into the cortex and converting into a steroidogenic phenotype. Delta-like homologue 1 (Dlk1), a member of the Notch/Delta/Serrate family of epidermal growth factor-like repeat-containing proteins, has a well-established role in inhibiting adipocyte differentiation. We demonstrate that Shh and Dlk1 are coexpressed in the outer undifferentiated zone of the male rat adrenal and that Dlk1 signals to the adrenal capsule, activating glioma-associated oncogene homolog 1 transcription in a β1 integrin- and Erk1/2-dependent fashion. Moreover, Shh and Dlk1 expression inversely correlates with the size of the zona glomerulosa in rats after manipulation of the renin-angiotensin system, suggesting a role in the ho...

Journal ArticleDOI
TL;DR: Activation of the local adrenal renin system is probably causative for the severely disturbed steroid hormone secretion of neonatal Task3(-/-) mice.
Abstract: Task3 K(+) channels are highly expressed in the adrenal cortex and contribute to the angiotensin II and K(+) sensitivity of aldosterone-producing glomerulosa cells. Adult Task3(-/-) mice display a partially autonomous aldosterone secretion, subclinical hyperaldosteronism, and salt-sensitive hypertension. Here, we investigated the age dependence of the adrenal phenotype of Task3(-/-) mice. Compared with adults, newborn Task3(-/-) mice displayed a severe adrenal phenotype with strongly increased plasma levels of aldosterone, corticosterone, and progesterone. This adrenocortical dysfunction was accompanied by a modified gene expression profile. The most strongly up-regulated gene was the protease renin. Real-time PCR corroborated the strong increase in adrenal renin expression, and immunofluorescence revealed renin-expressing cells in the zona fasciculata. Together with additional factors, activation of the local adrenal renin system is probably causative for the severely disturbed steroid hormone secretion of neonatal Task3(-/-) mice. The changes in gene expression patterns of neonatal Task3(-/-) mice could also be relevant for other forms of hyperaldosteronism.

Journal ArticleDOI
TL;DR: The identification of the complete set of SF-1 target genes will be of great importance to open new avenues for therapeutic intervention in adrenal diseases.

Journal ArticleDOI
TL;DR: Severe adrenocortical atrophy was associated typically with lymphoplasmacytic infiltration and nearly complete loss of cortical cells; however, the zona glomerulosa was partially spared in three dogs with lymphoplastic adrenalitis and severe cortical atrophy.

Journal ArticleDOI
TL;DR: Findings suggest a relatively greater tonic inhibition at hypothalamic–pituitary sites through the mu‐opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.
Abstract: The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

Journal ArticleDOI
09 Apr 2013-Stress
TL;DR: Data indicate an enhanced adrenal availability of and capacity to mobilize cholesterol in chronic psychosocially-stressed mice, contributing to their increased in vivo corticosterone response during acute heterotypic stressor exposure.
Abstract: Mice exposed to chronic subordinate colony housing (CSC, 19 days) show an exaggerated adrenal corticosterone response to an acute heterotypic stressor (elevated platform (EPF), 5 min) despite no difference from EPF-exposed single-housed control (SHC) mice in corticotropin (ACTH) secretion. In the present study, we asked the question whether this CSC-induced increase in adrenal capability to produce and secrete corticosterone is paralleled by an enhanced adrenal availability and/or mobilization capacity of the corticosterone precursor molecule cholesterol. Employing oil-red staining and western blot analysis we revealed comparable relative density of cortical lipid droplets and relative protein expression of hormone-sensitive lipase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and low-density lipoprotein receptor (LDL-R) between CSC and SHC mice. However, relative protein expression of the scavenger receptor class B type 1 (SR-BI) was increased following CSC exposure. Moreover, analys...

Journal ArticleDOI
TL;DR: Probably through increasing HPA axis activity, type1 diabetes-induced hyperglycemia leads to adrenal hypertrophy and increase the hormonal output of adrenal gland in both types of diabetes.
Abstract: Diabetes is one of the most common endocrine disorders characterized by hyperglycemia due to defects in insulin secretion, insulin function, or both. Causing dysfunction in the body general metabolism, diabetes-induced chronic hyperglycemia leads to alterations in those endocrine glands involved in regulating the body metabolism. In this line, the present study has been conducted to investigate the effects of type 1 and type 2 diabetes on the structural changes and hormonal output of the adrenal cortex in male Wistar rat. Eighteen male Wistar rats were divided into three groups including control, experimental type 1 diabetes (subcutaneous injection of 135 mg/kg alloxan) and experimental type 2 diabetes (8 weeks treatment with drinking water containing 10% fructose). Two months after the induction of both types of diabetes, the level of blood biochemical factors (glucose, insulin, cortisol, triglycerides, cholesterol, LDL, and HDL) were measured. Structural changes of the adrenal cortex were then evaluated, using stereological techniques. Serum biochemical analysis showed significant difference in the levels of glucose, triglycerides, insulin and cortisol in experimental groups, compared to the control. The results of structural alterations were also indicative of increase in adrenal cortex volume in both types of diabetes. Probably through increasing HPA axis activity, type1 diabetes-induced hyperglycemia leads to adrenal hypertrophy and increase the hormonal output of adrenal gland.

Journal ArticleDOI
TL;DR: It is concluded that IH elicits a significant pituitary-adrenal response and significantly alters glucose homeostasis in the neonatal rat and the quantitative and qualitative characteristics of these responses depend on developmental age.
Abstract: Apnea, the temporary cessation of respiratory airflow, is a common cause of intermittent hypoxia (IH) in premature infants. We hypothesized that IH elicits a stress response and alters glucose home...

Journal ArticleDOI
TL;DR: Novel data demonstrate that QRFP induces adrenal steroidogenesis in vitro by regulating key steroidogenic enzymes involving MAPK/PKC and Ca(2+) signaling pathways.
Abstract: Hormonal regulation of adrenal function occurs primarily through activation of GPCRs. GPCRs are central to many of the body's endocrine and neurotransmitter pathways. Recently, it was shown that activation of GPR103 by its ligand QRFP induced feeding, locomotor activity, and metabolic rate, and QRFP is bioactive in adipose tissue of obese individuals. Given that the adrenal gland is a pivotal organ for energy balance and homeostasis, we hypothesized that GPR103 and QRFP are involved in steroidogenic responses. Using qRT-PCR and immunohistochemistry, we mapped both GPR103 and QRFP in human fetal and adult adrenal gland as well as rat adrenals. Both were primarily localized in the adrenal cortex but not in the medulla. Activation of GPR103 in human adrenocortical H295R cells led to a decrease in forskolin-increased cAMP and an increase of intracellular Ca(2+) levels. In addition, treatment of H295R cells with QRFP induced aldosterone and cortisol secretion as measured by ELISA. These increases were accompanied by increased expression and activity of StAR, CYB11B1, and CYP11B2 as assessed by qRT-PCR and luciferase reporter assay, respectively. Using specific inhibitors, we also demonstrated that aldosterone induction involves MAPK, PKC, and/or T-type Ca(2+) channel-dependent pathways. These novel data demonstrate that QRFP induces adrenal steroidogenesis in vitro by regulating key steroidogenic enzymes involving MAPK/PKC and Ca(2+) signaling pathways.

Journal ArticleDOI
TL;DR: A role for miRNA-mediated regulation of a subset of genes that are essential for normal adrenal growth and homeostasis is suggested.
Abstract: MicroRNAs (miRNAs) are small, endogenous, non-protein-coding RNAs that are an important means of posttranscriptional gene regulation. Deletion of Dicer, a key miRNA processing enzyme, is embryonic lethal in mice, and tissue-specific Dicer deletion results in developmental defects. Using a conditional knockout model, we generated mice lacking Dicer in the adrenal cortex. These Dicer-knockout (KO) mice exhibited perinatal mortality and failure of the adrenal cortex during late gestation between embryonic day 16.5 (E16.5) and E18.5. Further study of Dicer-KO adrenals demonstrated a significant loss of steroidogenic factor 1-expressing cortical cells that was histologically evident as early as E16.5 coincident with an increase in p21 and cleaved-caspase 3 staining in the cortex. However, peripheral cortical proliferation persisted in KO adrenals as assessed by staining of proliferating cell nuclear antigen. To further characterize the embryonic adrenals from Dicer-KO mice, we performed microarray analyses for both gene and miRNA expression on purified RNA isolated from control and KO adrenals of E15.5 and E16.5 embryos. Consistent with the absence of Dicer and the associated loss of miRNA-mediated mRNA degradation, we observed an up-regulation of a small subset of adrenal transcripts in Dicer-KO mice, most notably the transcripts coded by the genes Nr6a1 and Acvr1c. Indeed, several miRNAs, including let-7, miR-34c, and miR-21, that are predicted to target these genes for degradation, were also markedly down-regulated in Dicer-KO adrenals. Together these data suggest a role for miRNA-mediated regulation of a subset of genes that are essential for normal adrenal growth and homeostasis.

Journal ArticleDOI
01 Nov 2013-Peptides
TL;DR: It is shown for the first time that expression of (P)RR is elevated in tumor tissues of APAs, raising the possibility that ( P)RR may play pathophysiological roles in AP as, such as aldosterone secretion and cell proliferation.