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Insulin resistance is not simply a problem of decreased glucose uptake in response to insulin, but a multifaceted syndrome that significantly increases the risk for cardiovascular disease. Insulin resistance is strongly associated with arterial hypertension and a pathogenetic role in the development of arterial hypertension has been suggested. One question that remains open concerns the clinical approach to insulin-resistant patients. Observational and clinical trial data suggest that lifestyle changes including weight reduction and regular physical activity can improve insulin sensitivity and reduce the incidence and mortality of cardiovascular disease. Daily physical activity of moderate intensity for 30min has a cardioprotective effect and reduces insulin resistance, independent of the effect on body weight. A pharmacological therapy for insulin resistance reducing cardiovascular disease remains to be defined. Concerning the antihypertensive therapy of insulin-resistant hypertensive patients, most hypertensive guidelines fail to provide specific advice. [Copyright &y& Elsevier]

Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different investigators, suggesting that an abnormal secretion of aldosterone in obesity contributes to the development of arterial hypertension in obese subjects. The mechanisms proposed to explain this abnormal aldosterone production mainly involve the adipose renin–angiotensin system, an indirect effect of increased fatty acids, and direct adrenal stimulation by adipocyte secretory products. Indeed, adipose mineralocorticoid-stimulating activity was recently observed in isolated human adipocytes, suggesting a hitherto unknown direct involvement of adipose tissue in the regulation of blood pressure in obesity. [Copyright &y& Elsevier]

It is increasingly clear that significant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inflammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulation. [Copyright &y& Elsevier]

Abstract: Endothelial cells play an important role in the development and functioning of endocrine tissue and endothelial cell-derived factors have been shown to regulate mineralocorticoid release in bovine adrenal cells. In the present study, we analysed the role of human endothelial cells in the synthesis and release of aldosterone from adrenocortical cells (NCI-H295R). Endothelial cell-induced aldosterone release was rapid and lasted as a long-term effect over a period of 48h. This stimulant effect was influenced by the duration of endothelial cell conditioning and decreased linearly with increasing dilutions of the conditioned medium. At the molecular level, an increase in the mRNA transcripts of aldosterone synthase and StAR could be observed. Cellular interaction with endothelial cell-factors enhanced the activation of CRE, and the promoter activity of both StAR and SF-1 reporter genes. In conclusion, human endothelial cells are important intra-adrenal regulators of human aldosterone synthesis and release. [Copyright &y& Elsevier]

The adrenal is a highly plastic organ with the ability to adjust to physiological needs by adapting hormone production but also by generating and regenerating both adrenocortical and adrenomedullary tissue. It is now apparent that many adult tissues maintain stem and progenitor cells that contribute to their maintenance and adaptation. Research from the last years has proven the existence of stem and progenitor cells also in the adult adrenal medulla throughout life. These cells maintain some neural crest properties and have the potential to differentiate to the endocrine and neural lineages. In this article, we discuss the evidence for the existence of adrenomedullary multi potent progenitor cells, their isolation and characterization, their differentiation potential as well as their clinical potential in transplantation therapies but also in pathophysiology. [ABSTRACT FROM AUTHOR]

Abstract: Dehydroepiandrosterone producing adrenocortical zona reticularis and the adrenal medulla are in direct contact and are highly intermingled in many species. This results in potentially strong paracrine influences of high local dehydroepiandrosterone concentrations on the adrenal medulla. Dehydroepiandrosterone has neuroprotective properties and increases neural stem cell proliferation and neurogenesis. Therefore, we aimed to establish its effects on chromaffin progenitor cell proliferation and differentiation. Previously, we successfully isolated chromaffin progenitors from bovine adrenal medulla in spherical cultures, so-called chromospheres. Seven days treatment of chromospheres with dehydroepiandrosterone at high concentrations (100μM) hampered proliferation of chromaffin progenitors. Under differentiation conditions, dehydroepiandrosterone in the presence of retinoic acid, increased tyrosine hydroxylase and decreased dopamine-β-hydroxylase mRNA expression. In addition, there was a tendency to increase dopamine contents. Dehydroepiandrosterone/retinoic acid is therefore suggested to induce dopaminergic differentiation from chromaffin progenitor cells. Furthermore, the high dehydroepiandrosterone concentrations present in the fetal and adult adrenal may play an important role in adrenomedullary cell proliferation and differentiation. [Copyright &y& Elsevier]

Abstract: Dehydroepiandrosterone sulfate is classically seen as an inactive reservoir for the production of dehydroepiandrosterone. Steroid sulfatase is the enzyme that catalyzes the hydrolysis of dehydroepiandrosterone sulfate to dehydroepiandrosterone, which can then be further metabolized to other steroid hormones. Recent studies, however, indicate that dehydroepiandrosterone sulfate can mediate biological effects without being converted to dehydroepiandrosterone. This study aims to evaluate whether dehydroepiandrosterone sulfate itself influences the differentiation of PC-12 cells or if its desulfation to dehydroepiandrosterone is required. dehydroepiandrosterone and dehydroepiandrosterone sulfate both influence the differentiation of chromaffin PC-12 cells. Blocking steroid sulfatase activity and thereby the conversion of dehydroepiandrosterone sulfate to dehydroepiandrosterone by the enzyme blocker estrone sulfamate showed that the effect of dehydroepiandrosterone sulfate is independent of its conversion to dehydroepiandrosterone. Dehydroepiandrosterone sulfate, similar to dehydroepiandrosterone, reduced nerve growth factor-induced neurite outgrowth of PC-12 cells and the expression of synaptosomal-associated membrane protein of 25kDa, increased the expression of chromogranin A and significantly increased dopamine release of PC-12 cells. In addition, dehydroepiandrosterone sulfate, dehydroepiandrosterone and membrane impermeable dehydroepiandrosterone-BSA all significantly reduced NGF-induced MAPK ERK1/2 signaling after 5min. In summary, this study provides evidence that dehydroepiandrosterone sulfate, independent of its conversion to dehydroepiandrosterone, directs PC-12 cells’ differentiation to a neuroendocrine direction. Furthermore, employing membrane-impermeable dehydroepiandrosterone-BSA indicates the involvement of plasma-membrane bound receptors. [Copyright &y& Elsevier]

Abstract: Rapid activation of adrenal steroid release plays a pivotal role in an organism''s first line of defense during sepsis. Adrenal gland function is often suppressed in critically ill patients and negatively impacts the overall survival rate. Increasingly, experimental and clinical evidence suggests that Toll-like receptors (TLRs), components of the innate immune system, play a key role in the mediation of systemic responses to invading pathogens during sepsis. In the present study, we aimed to elucidate the effect of TLR2, TLR4 and CD14 upregulation on adrenocortical cell steroidogenesis. We found that TLR4 and CD14 but not TLR2 overexpression in NCI-H295R cells inhibited basal and acute cortisol and aldosterone production. This effect could be partially explained by reduced expression of enzymes involved in the synthesis of latter steroids – CYP11B1 and CYP11B2. Together, these data suggest that TLR upregulation in the steroid producing cells may be involved in the adrenal gland dysfunction during sepsis. [Copyright &y& Elsevier]

Abstract: The major source for dehydroepiandrosterone (DHEA) and its sulphate compound DHEA-S is the inner zone of the adrenal cortex, which is in direct contact to adrenomedullary chromaffin cells. Due to their close proximity, direct interactions of DHEA and DHEA-S with chromaffin cells during adrenal gland development and throughout the whole life span are hypothesized. A possible direct effect of DHEA-S and the cellular and molecular mechanisms of DHEA-S action on chromaffin cells remain unresolved. Therefore, in this study, we aimed at clarifying DHEA-S effects and mechanisms of action on rat chromaffin PC12 cells. DHEA-S (10−6 mol/l) inhibited nerve growth factor (NGF, 20ng/ml)-induced cell proliferation by 66% (n =4, p <0.001). In NGF-stimulated cells, neuronal differentiation was inhibited by DHEA-S, as demonstrated by a 22% reduction (n =3; p <0.05) of neuronal differentiation marker expression, synaptosome-associated protein of 25kDa (SNAP-25), and a 59% (n =6; p <0.001) decrease in neurite outgrowth. Moreover, DHEA-S stimulated expression of endocrine marker chromogranin A (CgA) by 31% (n =4; p <0.05 vs. control) and catecholamine release from NGF-treated PC12 cells by 229% (n =3–5; p <0.001), indicating a DHEA-S-induced shift towards neuroendocrine differentiation. On a molecular level, DHEA-S diminished NGF-induced ERK1/2 phosphorylation. Taken together, DHEA-S inhibited NGF-induced proliferation and neuronal differentiation and shifted cells towards a more endocrine phenotype. Interference of DHEA-S with NGF-stimulated ERK1/2 activation might be involved in this effect. Our study provides support for the notion that adrenocortical-derived DHEA-S impacts adrenomedullary chromaffin cells during development and differentiation. [Copyright &y& Elsevier]

Abstract: During sepsis, an intact adrenal gland glucocorticoid stress response is critical for survival. Recently, we have shown that Toll-like receptors, particularly TLR2 and TLR4, are crucial in HPA axis regulation following inflammation, establishing a direct link between bacterial and viral ligands and the endocrine stress response. However, the exact role which TLRs play in adrenal homeostasis and malfunction is not yet sufficiently known. Using quantitative real-time PCR, confocal microscopy and the NF-κB reporter gene assay, we aimed to analyse both, expression and function of all relevant TLRs in the human adrenocortical cell line—NCI-H295R and adrenal cells in primary culture. Our results demonstrate a differential expression pattern of TLR1–9 in human adrenocortical cells as compared to immune cells and adrenocortical cancer cells. Consequently, activation of these cells by bacterial ligands leads to differential induction of cytokines including IL6, IL8 and TNF-α. Therefore, Toll-like receptors expression and function is a novel feature of the adrenal stress system contributing to adrenal tissue homeostasis, regeneration and tumorigenesis. [Copyright &y& Elsevier]

Summary: Aldosterone synthesis is primarily regulated by angiotensin II and potassium ions. In addition, endothelial cell-secreted factors have been shown to regulate mineralocorticoid release. We analyzed the pathways that mediate endothelial cell-factor-induced aldosterone release from adrenocortical cells, NCI-H295R using endothelial cell-conditioned medium (ECM). The cAMP antagonist Rp-cAMP caused a 44% decrease in the ECM-induced aldosterone release but inhibition of cAMP-dependent PKA had no effect on aldosterone release. Interestingly, inhibition of cAMP-regulated guanine nucleotide exchange factor Epac with brefeldin-A decreased the ECM-induced aldosterone release by 45%. Similarly, inhibition of p38 MAP-kinase; PI-3-kinase and PKB significantly reduced the ECM-induced aldosterone release whereas inhibition of ERK1/2 and PKC did not decrease aldosterone release. These results provide evidence for the existence of a cAMP-dependent but PKA-independent pathway in mediating the ECM-induced aldosterone release and the significant influence of more than one signaling mechanism. [Copyright &y& Elsevier]

Abstract: The A-ZIP/F-1 transgenic mouse is a model of lipoatrophic diabetes with severe insulin resistance, hyperglycemia and hyperlipidemia. Recently, a regulatory role of adipose tissue on adrenal gland function and blood pressure has been suggested. To further explore the importance of adipose tissue in the regulation of adrenal function and blood pressure, we studied this mouse model of lipodystrophy. A-ZIP/F-1 mice exhibit significantly elevated systolic and diastolic blood pressure values despite lack of white adipose tissue and its hormones. Furthermore, A-ZIP/F-1 lipoatrophic mice have a significant reduction of adrenal zona glomerulosa, while plasma aldosterone levels and aldosterone synthase mRNA expression remain unchanged. On the other hand, lipoatrophic mice present elevated corticosterone levels but no adrenocortical hyperplasia. Ultrastructural analysis of adrenal gland show significant alterations in adrenocortical cells, with conformational changes of mitochondrial internal membranes and high amounts of liposomes. In conclusion, lipodystrophy in A-ZIP/F-1 mice is associated with hypertension, possibly due to hypercorticosteronemia and/or others metabolic–vascular changes. [Copyright &y& Elsevier]