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Biomedical subjects

M Ehrhart-Bornstein

Publications and source records attributed to M Ehrhart-Bornstein.

At least 19 recordsLinked to original sources
PubMed2007

Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway.

CONTEXT: Obesity is associated with hypersecretion of cortisol and aldosterone and a high prevalence of arterial hypertension. At the cellular level, a direct effect of adipocytes on the expression of the steroidogenic acute regulatory (StAR) protein, a regulator of cortisol and aldosterone synthesis, and on aldosterone and cortisol secretion has been shown. However, the molecular mechanisms mediating this effect are not known. OBJECTIVE: Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. Therefore, we investigated whether adipocytes stimulate adrenal steroidogenesis through the activation of Wnt-signaling. RESULTS: Using immunohistochemistry, we detected the expression of frizzled and beta-catenin in the adult human adrenal cortex. Transient transfection of a Wnt-dependent reporter-gene into adrenal NCI-H295R cells showed an induction of Wnt-mediated transcription to 308% after treatment with human fat cell-conditioned medium (FCCM). This finding was paralleled by an induction of StAR promoter activity (420%) by FCCM. The induction of StAR promoter activity by FCCM was inhibited by 49% when Wnt-signaling was blocked by the soluble Wnt-antagonist secreted Frizzled-Related-Protein-1 (sFRP-1). Overexpression of a constitutively active mutant of beta-catenin induced the transcription of the StAR promoter (440%). beta-Catenin and FCCM induced SF-1-mediated transcription at a SF-1-driven reporter gene (420 and 402%, respectively). Furthermore, the secretion of aldosterone and cortisol by NCI-H295R cells induced by FCCM was significantly inhibited by the Wnt-antagonist sFRP-1. CONCLUSION: These data indicate that the Wnt-signaling pathway is one of the mechanisms mediating the effects of fat cells on adrenal StAR transcription and aldosterone and cortisol secretion.

Adipocytes↗
PubMed2006

Metabolic syndrome and the endocrine stress system.

Obesity constitutes one of the most serious public health problems, with rapidly increasing prevalence in western societies. Consequently, metabolic syndrome, a condition strongly associated with obesity, has become an epidemic problem. Recent studies have implicated chronic alterations to the stress system as playing a major role in the metabolic syndrome's pathophysiology. This brief review discusses the role of stress and hypothalamic-pituitary-adrenal axis dysfunction in the development of metabolic syndrome as well as new insights into the crosstalk between adipose tissue and endocrine stress system.

Adipocytes↗
PubMed2006

Vascular-adrenal niche--endothelial cell-mediated sensitization of human adrenocortical cells to angiotensin II.

Alterations in both vasculature and renin-angiotensin-aldosterone system are a consistent finding in the metabolic syndrome. Adrenal tissue is highly vascularized and encounters blood flow, exceeding by far the volume expected for its size. Endothelial cells in the adrenal vasculature are therefore a major cellular component of adrenocortical tissue. The aim of the study was to analyze the cellular interaction between endothelial and steroid producing cells, focusing on endothelial cell-factor-mediated activation of aldosterone synthesis. The interaction between human endothelial (HUVECs) cell-conditioned medium and human adrenocortical (NCI-H295R) cells IN VITRO induced a significant surge in aldosterone secretion. The endothelial cell-conditioned medium together with angiotensin II and forskolin also potentiated aldosterone release by 1.5-fold and 2.6-fold, respectively, while preincubation of NCI-H295R cells for 24 h with endothelial cell-conditioned medium enhanced and sensitized the response of NCI-H295R to subsequent angiotensin II and forskolin stimuli by 2.5-fold and 2.2-fold, respectively. The increase in aldosterone release after preincubation with endothelial cell-conditioned medium was sensitive to cycloheximide and KN-93. Cellular conditioning with endothelial-cell factors exerts a hitherto unknown paracrine regulation of aldosterone production in human adrenocortical cells. This interaction may contribute to altered basal aldosterone release and have a role in patients with hypertension.

Adrenal Cortex↗
PubMed2006

Increased aldosterone/renin quotient in obese hypertensive women: a novel role for low-density lipoproteins?

Obesity, especially visceral obesity, is strongly associated with arterial hypertension. Indeed, obesity hypertension has to be considered as the most common form of essential hypertension. However, the exact nature of the relationship between obesity and increased blood pressure remains poorly understood. Involvement of renin-independent mechanisms has been suggested in adrenal stimulation of aldosterone secretion in obese patients. This investigation examined the plasma levels of renin, aldosterone, insulin, and HDL and LDL in obese hypertensive and obese normotensive women. The group of hypertensive obese women showed significantly reduced plasma levels of renin and increased aldosterone/renin quotient (ARQ) compared to obese normotensive women. Plasma aldosterone levels were not significantly different between hypertensive and normotensive obese women. In addition, plasma levels of LDL-cholesterol in the hypertensive obese group were significantly increased in comparison to the obese normotensive group. No differences were observed in HDL-cholesterol or total cholesterol/HDL-C ratios between the two groups. We therefore examined the effect of LDL on angiotensin II-stimulated aldosterone release from human adrenocortical H295R cells. Treatment of adrenocortical cells with LDL led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production, so the increased aldosterone/renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors.

Adolescent↗
PubMed2006

Role of DHEA and growth factors in chromaffin cell proliferation.

Dehydroepiandrostreone (DHEA) is a neuroactive steroid produced by the inner layer of the adrenal cortex close to the adrenomedullary cells. Chromaffin cell growth and proliferation are under the control of insulin-like growth factor II (IGF-II) and basic fibroblast growth factor (bFGF). The aim of the present study was to examine the role of DHEA on chromaffin cell proliferation induced by IGF-II and bFGF. In our model, DHEA significantly decreased IGF-II-induced proliferation by 48.7%, whereas it did not affect the proliferation induced by bFGF. These data suggest that DHEA exerts a paracrine function in the control of chromaffin cell growth.

Cell Proliferation↗
PubMed2005

Newly discovered endocrine functions of white adipose tissue: possible relevance in obesity-related diseases.

During recent years our view of adipose tissue has been revolutionized. White adipose tissue (WAT) is no longer seen as mere energy store or provider of thermal and mechanical insulation. Neglect of WAT has been overcome by surprising discoveries in recent years, changing the view of this tissue towards a highly endocrine organ that is involved in a wide variety of physiological and pathophysiological processes. In this brief article we will focus on new developments in adipocyte and WAT biology. The appreciation of WAT as an endocrine organ will provide the basis for new and promising perspectives in the management of obesity and obesity-related diseases including diabetes, mellitus type II and arterial hypertension.

Adipose Tissue↗
PubMed2004

Mechanisms of obesity-related hypertension.

Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension and cardiovascular disease. Although the importance of obesity as a cause of hypertension is well established, the molecular basis of the relationship between obesity and increased blood pressure remains poorly understood. This brief review examines the association between obesity and hypertension along with the mechanisms proposed to explain this association, while presenting evidence of a direct causal effect of adipose tissue in the development of hypertension through the involvement of the adrenal cortex.

Adipose Tissue↗
PubMed2003

Human adipocytes secrete mineralocorticoid-releasing factors.

Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin (2 x 10(-5) M). On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99 degrees C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass >50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass <50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.

Adipocytes↗
PubMed2003

The prototypic antidepressant drug, imipramine, but not Hypericum perforatum (St. John's Wort), reduces HPA-axis function in the rat.

Dysregulation in corticotropin-releasing hormone (CRH) secretion in the hypothalamus-pituitary-adrenal (HPA) axis may be involved in the etiology of major depressive disorder (MDD). Chronic therapy with standard antidepressant drugs, such as imipramine, can downregulate HPA axis function, indicating that the HPA axis may be an important target for antidepressant action. We tested several doses of a standardized commercial preparation of Hypericum perforatum plant extract (popularly known as St. John's Wort), a medicinal herb used for treating mild depressive symptoms, to determine whether it also modulated HPA axis function. Chronic imipramine treatment (daily injections for 8 weeks) of male Sprague-Dawley rats significantly downregulated circulating plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone compared to animals treated with saline. However, chronic St. John's Wort treatment (daily gavage for 8 weeks) had no effect on plasma ACTH or corticosterone, even at the highest doses tested. Our results confirm previous findings that imipramine may have significant peripheral HPA axis-mediated effects. However, our data does not support any role for H. perforatum in modulation of HPA axis function, suggesting that alternative pathways may be involved in mediating its antidepressant effects.

Adrenal Glands↗
PubMed2000

Expression of adrenocortical steroidogenic acute regulatory (StAR) protein is influenced by chromaffin cells.

Cell-cell interactions are crucial role for the proper functioning of endocrine glands. We recently demonstrated that interactions of chromaffin and cortical cells are important for adrenocortical steroidogenesis. However, the molecular mechanisms have not been elucidated and it is unclear if this involves acute and/or chronic processes. By Northern analysis and the quantitative technique of TaqMan PCR we investigated whether chromaffin cells influence the regulation of StAR and the peripheral benzodiazepine receptor (PBR), both required for the rate-limiting step, the delivery of cholesterol to the inner mitochondrial membrane. StAR mRNA levels in bovine adrenocortical cells were increased by incubation with chromaffin cell-conditioned medium (CCM). Short-term treatment for 4 h resulted in a greater stimulation (229+/-29% of basal, mean+/-SEM) than did longer incubation times of 8 h and 5 days (159+/-13 and 177+/-24%). Neither short nor a long-term treatment affected PBR expression. Consistently, the major secretion of chromaffin cells, epinephrine dose-dependently stimulated StAR expression with no effect on PBR mRNA. In conclusion, adrenomedullary secretory products are not necessary for the maintenance of PBR expression but facilitate steroid biosynthesis by increasing StAR mRNA expression and therefore can account for an ACTH-independent regulation of the rate-limiting step in steroidogenesis.

Adrenal Cortex↗
PubMed2000

Basic and clinical aspects of intraadrenal regulation of steroidogenesis.

The adrenal gland combines essential components of the autonomic nervous system and the HPA axis in close contact. From morphological analyses employing immunohistochemistry, in situ hybridization, the novel technique of laser capture microdissection, and electron microscopy, it has been has shown that the chromaffin cells of the adrenal medulla and the steroid-producing cells of the adrenal cortex are extensively intermingled and functionally interrelated. In in vitro studies, a variety of regulatory factors produced and released by the adrenal medulla were identified as playing an important role in modulating adrenocortical function. An isolated adrenocortical cell deprived of its tissue integrity, input from the nervous system, or intercellular communication with chromaffin, vascular, and immune cells of the adrenal gland, loses its normal capacity to produce glucocorticoids and to adequately respond to the homeostatic challenges of stress. Adrenocortical cells in co-culture with chromaffin cells produced ten times more glucocorticoids than the same number of pure adrenocortical cells and demonstrated marked up-regulation in the mRNA expression of cytochrome p450 enzymes and STAR in the co-culture, while this expression was down-regulated in isolated cells. Transgenic animal models of over-expression or deletion of enzymes involved in catecholamine synthesis, as well as of altered function of components of the HPA axis, provide evidence that the mutual interdependence of the sympatho-adrenal system and the HPA axis at the level of the adrenal gland is of physiologic relevance in vivo. Alterations in intercellular communications, local production of neuropeptides, growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal cells have been implicated in adrenal cell growth, development, hyperplasia, tumor formation, autonomous hormone production, and autoimmune disease. Moreover, we described a direct cellular interaction of lymphocytes with adrenal cells as a novel non-cytokine mediated mechanism of immune endocrine interactions. Highlighting the importance of the extra-pituitary mechanisms of adrenocortical regulation, be them neural or immune, is a worthwhile starting point for a more complete analysis of the human stress system in vivo.

Adrenal Cortex↗
PubMed2000

Neurotransmitters and neuropeptides in the differential regulation of steroidogenesis in adrenocortical-chromaffin co-cultures.

Adrenocortical steroidogenesis is regulated in addition to a central regulation via the hypothalamus-pituitary-adrenal axis by intra-adrenal mechanisms involving the adrenal medulla. We could previously show that adrenocortical steroidogenesis is stimulated by co-culturing bovine adrenocortical cells with medullary chromaffin cells. This stimulation was due to soluble factors released from the chromaffin cells under basal, unstimulated conditions and involved the increased expression of P450 enzymes, StAR and de novo protein synthesis. In the present study we analyzed the differential regulation of the three cortical zones and characterized secretagogues involved in this stimulation. While cortisol and androstenedione release were increased 10 fold by incubation with chromaffin cell-conditioned medium, aldosterone secretion was not influenced. 80% of the stimulation proved to be due to adrenomedullary epinephrine, norepinephrine, ACTH, PACAP and PG-dependent mechanisms. Other adrenomedullary secretory products, serotonin, Met-enkephalin, Leu-enkephalin, galanin, CGRP, substance P, VIP or NPY did not stimulate steroidogenesis in this system. Our data show that adrenomedullary cells differentially regulate the three adrenocortical zones. This stimulation predominantly depended on epinephrine, norepinephrine, PACAP, and ACTH released from the chromaffin cells and prostaglandin-dependent mechanisms such as interleukin-1.

Adrenal Cortex↗
PubMed1999

Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress.

Antalarmin is a pyrrolopyrimidine compound that antagonizes corticotropin-releasing hormone (CRH) type 1 receptors (CRHR1). In order to assess the effects of antalarmin treatment on hypothalamic-pituitary-adrenal (HPA) function we measured the plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in animals treated with either antalarmin or vehicle for 1 week or for 8 weeks. We found that antalarmin treatment for 1 week did not affect basal concentrations of ACTH or corticosterone. In contrast, treatment for 8 weeks significantly lowered basal ACTH and corticosterone concentrations and also significantly decreased the basal corticosterone to ACTH ratio, indicating decreased basal adrenocortical responsiveness to ACTH. However, immobilization stress resulted in ACTH and corticosterone concentrations that were the same in animals treated with vehicle or antalarmin for either 1 or 8 weeks. We conclude that even though 8-week antagonism of CRHR1 by the non-peptide antalarmin blunts basal concentrations of ACTH and corticosterone, and affects the adrenal responsiveness to ACTH, it does not blunt the HPA response to acute stress, and it does not appear to cause stress-induced adrenal insufficiency.

Adrenocorticotropic Hormone↗
PubMed1999

Lack of leptin suppression in response to hypersecretion of catecholamines in pheochromocytoma patients.

Leptin is a major regulator of body weight and energy balance and is subject to a variety of regulatory inputs. From several previous studies, catecholamines have been suggested to exert an inhibitory influence on leptin production in animals. In the present study, we analyzed leptin levels in relation to catecholamine hypersecretion in 27 human pheochromocytoma patients. A 10-fold increase in circulating norepinephrine (P < .0001) did not result in suppression of plasma leptin in the patients compared with normal controls (median and interquartile range, 4.3 ng/mL [2.4 to 6.8] v 2.2 ng/mL [1.9 to 3.0] in men and 18.6 [12.3 to 27.0] v 11.4 [10.1 to 15.9] in women). Correlation analysis indicated a significant association of leptin with epinephrine in normal subjects (r = -.81, P < .0001), but not in pheochromocytoma patients. Leptin was not related to norepinephrine in either group. In conclusion, our data suggest that a chronic elevation of catecholamines does not cause suppression of leptin secretion in patients with pheochromocytoma. This lack of effect may be attributable to the development of tolerance of adipose tissue leptin production to catecholamines.

Adrenal Gland Neoplasms↗
PubMed1999

Local renin-angiotensin system is involved in K+-induced aldosterone secretion from human adrenocortical NCI-H295 cells.

NCI-H295, a human adrenocarcinoma cell line, has been proposed as a model system to define the role of the renin-angiotensin system in the regulation of aldosterone production in humans. Because the precise cellular localization of the components of the renin-angiotensin system in human adrenal cortical cells remains unclear, we investigated their localization in this defined cell system. NCI-H295 cells expressed both angiotensinogen and renin as shown by reverse transcriptase polymerase chain reaction and immunohistochemistry. Human angiotensin-converting enzyme (ACE) was not detectable by immunocytochemistry, ACE binding, or reverse transcriptase polymerase chain reaction. However, 3.5 mmol/L K+ stimulated the formation of both angiotensin I and angiotensin II 1. 9- and 2.5-fold, respectively, and increased aldosterone release 3. 0-fold. The K+-induced stimulation of aldosterone release was decreased by captopril and enalaprilat (24% and 26%, respectively) and by the angiotensin type 1 (AT1)-receptor antagonist losartan (28%). Angiotensin II-induced stimulation of aldosterone release was abolished by losartan treatment. Specific [125I]Sar1-angiotensin II binding was detected by receptor autoradiography. The binding of [125I]Sar1-angiotensin II was completely displaced by the AT1 antagonist losartan but not by the AT2 receptor ligand PD 123319, confirming the expression of angiotensin II AT1 receptors in NCI-H295 cells. Our results demonstrate that NCI-H295 cells express most of the components of the renin-angiotensin system. Our failure to detect ACE, however, suggests that the production of angiotensin II in NCI-H295 cells may be ACE independent. NCI-H295 cells are able to produce angiotensin II, and K+ increases aldosterone secretion in part through an angiotensin-mediated pathway. The production of angiotensin II in NCI-H295 cells demonstrates that this human cell line can be useful to characterize the role of locally produced angiotensin II in the regulation of aldosterone release.

Adrenal Cortex↗
PubMed1999

Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex.

Carney complex (CNC) is characterized by lentiginosis and myxomatosis together with a variety of endocrine, neural crest-derived, and other tumors, including primary pigmented nodular adrenocortical disease (PPNAD). PPNAD is characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue. The nature and origin of the tumors, including the myxomas and PPNAD, are unclear. In this study, seven paraffin-embedded PPNAD tumors, one skin myxoma, and two cell lines (one myxoma and one PPNAD) established from patients with CNC were stained with antisera for synaptophysin (SYN), neuron-specific enolase, chromogranin A, tyrosine hydroxylase, and the neural cell adhesion molecule (NCAM). In addition, one PPNAD specimen and one myxoma were analyzed by electron microscopy. The results showed that chromogranin A and tyrosine hydroxylase stained adrenomedullary tissue, but not the PPNAD nodules or the extranodular adrenal cortex. SYN, neuron-specific enolase, and NCAM also stained the medulla. PPNAD nodules and the PPNAD cell line, but not the extranodular adrenal cortex, stained intensely for SYN. The myxoma cell line, but not normal fibroblasts, stained for SYN and NCAM. Ultrastructural analysis of a PPNAD tumor and a skin myxoma revealed a well developed rough endoplasmic reticulum, prominent mitochondria, and vesicle-like structures dispersed throughout the cytoplasm. We conclude that immunostaining for SYN, a marker protein for neuroendocrine cells, clearly distinguishes PPNAD nodules from surrounding adrenocortical tissue and can be helpful in the detection of small nodules in apparently unaffected cortex. The cells of a cutaneous myxoma were also stained positive by two of the three neuroendocrine markers. Finally, both PPNAD and myxoma cells demonstrated ultrastructural features suggestive of neuroendocrine properties. These results support the previously suggested hypothesis that the genetic mechanism leading to CNC involves genes with a neuroendocrine role.

Adolescent↗