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    ABSTRACT: The development and maintenance of the zones of the adrenal cortex and their steroidal output is 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 co-expressed in the outer Undifferentiated Zone of the male rat adrenal and that Dlk1 signals to the adrenal capsule, activating Gli1 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 following manipulation of the renin-angiotensin system, suggesting a role in the homeostatic maintenance of the gland.
    Endocrinology 09/2013;
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    ABSTRACT: This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway.-Kola, B., Wittman, G., Bodnár, I., Amin, F., Lim, C. T., Oláh, M., Christ-Crain, M., Lolli, F., van Thuijl, H., Leontiou, C. A., Füzesi, T., Dalino, P., Isidori, A., Harvey-White, J., Kunos, G., Nagy, G. M., Grossman, A. B., Fekete, C., Korbonits, M. The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release.
    The FASEB Journal 08/2013;
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    ABSTRACT: Selective adenomectomy remains the first line treatment for Cushing's disease (CD), until recently by microscopic transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery (ETES) is emerging as a novel, less invasive treatment for pituitary adenomas and has become the optimal surgical approach. There are no published series of the treatment of paediatric CD by ETES and we report our centre's preliminary results. Retrospective analysis. Six paediatric patients (median age 15.8yr; range 11.7-17.0yr) fulfilled standard diagnostic criteria for CD. Preoperatively, no abnormality was identified on pituitary MR scanning in 3 (50%) patients, one had a macroadenoma. Bilateral petrosal sinus sampling demonstrated central ACTH secretion (IPS/P ACTH ratio ≥3.0, post-CRH) in 3/6 (50%) patients. The same neurosurgeon and endoscopic nasal surgeon undertook all the operations. Therapeutic outcome and rate of complications. Clinical recovery and biochemical 'cure' was achieved in 5 (83%) patients and a corticotroph adenoma was confirmed histologically in all cured cases. One case developed post-operative CSF leak requiring lumbar drain insertion and patching. At a mean interval of 4.7 years (0.1-10.8 yr) post-operatively, cured patients have shown no recurrence. One patient, with a large diffuse adenoma requiring more extensive surgery, has panhypopituitarism, another patient has GH and gonadotrophin deficiencies. Our experience shows that ETES for removing corticotroph adenomas in children, in most cases not visualised on MRI imaging, is minimally invasive and gave excellent postoperative recovery/results. In skilled hands this technique provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 06/2013;
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    ABSTRACT: Developmental signalling pathways are implicated in the formation and maintenance of the adrenal gland, but their roles are currently not well defined. In recent years it has emerged that Sonic hedgehog (Shh) and Wnt/β catenin signalling are crucial for the growth and development of the adrenal cortex. Here we demonstrate that Fibroblast growth factor receptor (Fgfr) 2 isoforms IIIb and IIIc are expressed mainly in the adrenal subcapsule during embryogenesis and that specific deletion of the Fgfr2 IIIb isoform impairs adrenal development, causing reduced adrenal growth and impaired expression of SF1 and steroidogenic enzymes. The hypoplastic adrenals also have thicker, disorganised capsules which retain Gli1 expression but no longer express Dlk1. Fgfr2 ligands were detected in both the capsule and the cortex, suggesting the importance of signalling between the capsule and the cortex in adrenal development.
    Molecular and Cellular Endocrinology 01/2013;
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    ABSTRACT: Ghrelin was originally identified as a growth hormone secretagogue, but later studies suggested that it plays an important role in the regulation of appetite and body weight. The implication of genetic variants of the ghrelin-ghrelin receptor axis in the determination of stature, appetite, body weight, glucose metabolism and eating disorders has been the focus of numerous small and larger studies. More recently, several studies have shown some involvement of ghrelin and growth hormone secretagogue receptor (GHSR) genetic variants in some cancers, or their role in the genetics of immune diseases or addictive behaviour. The overall results suggest that the effects of common genetic variants are lacking or modest, while rare sequence alteration may lead to disease status in individual patients. In this review we summarize the available data on the genetics of ghrelin axis in humans.
    Endocrine development 01/2013; 25:25-40.
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    ABSTRACT: The five melanocortin receptors (MCRs) named MC1R-MC5R have diverse physiological roles encompassing pigmentation, steroidogenesis, energy homeostasis and feeding behavior as well as exocrine function. Since their identification almost 20 years ago much has been learnt about these receptors. As well as interacting with their endogenous ligands the melanocortin peptides, there is now a growing list of important peptides that can modulate the way these receptors signal, acting as agonists, antagonists, and inverse agonists. The discovery of melanocortin 2 receptor accessory proteins as a novel accessory factor to the MCRs provides further insight into the regulation of these important G protein-coupled receptor.
    Frontiers in Endocrinology 01/2013; 4:9.
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    ABSTRACT: ACTH resistance is a rare disorder typified by familial glucocorticoid deficiency (FGD), a genetically heterogeneous disease. Previously, genetic defects in FGD have been identified in the ACTH receptor gene (MC2R), its accessory protein (MRAP) and the steroidogenic acute regulatory protein gene (STAR). The defective mechanisms here are failures in ACTH ligand binding and/or receptor trafficking for MC2R and MRAP and, in the case of STAR mutations, inefficient cholesterol transport to allow steroidogenesis to proceed. Novel gene defects in FGD have recently been recognised in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT). MCM4 is one part of a DNA repair complex essential for DNA replication and genome stability, whilst NNT is involved in the glutathione redox system that protects cells against reactive oxygen species. The finding of mutations in these two genes implicates new pathogenetic mechanisms at play in FGD, and implies that the adrenal cortex is exquisitely sensitive to replicative and oxidative stresses.
    Endocrine development 01/2013; 24:57-66.
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    ABSTRACT: Familial Glucocorticoid deficiency (FGD), in which the adrenal cortex fails to produce glucocorticoids, was first shown to be caused by defects in the receptor for ACTH (MC2R) or its accessory protein (MRAP). Certain mutations in the steroidogenic acute regulatory protein (STAR) can also masquerade as FGD. Recently mutations in mini chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT), genes involved in DNA replication and antioxidant defence respectively, have been recognised in FGD cohorts. These latest findings expand the spectrum of pathogenetic mechanisms causing adrenal disease and imply that the adrenal may be hypersensitive to replicative and oxidative stresses. Over time patients with MCM4 or NNT mutations may develop other organ pathologies related to their impaired gene functions and will therefore need careful monitoring.
    Molecular and Cellular Endocrinology 12/2012;
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    ABSTRACT: Background:  Chest circumference (CC) is suggested to be a good indicator of early life nutrition, but little is known on the heritability of CC. Thus we analysed the effects of genetic and environmental factors on the development of CC in Japanese infants. Methods:  CC was measured longitudinally from birth until 1 year of age in a cohort of 211 monozygotic and 160 dizygotic complete Japanese twin pairs born in 1989-2002. The data were analysed using applications of structural linear equation modelling for twin data. Results:  No sex-specific differences in the variance components were found. Environmental factors unique to each twin explained the major part of the variation of CC at birth whereas environmental factors shared by co-twins were more important at 1-3 months of age. From 3 months of age, the effect of genetic factors become steadily stronger and they explained the majority of the variation at 1 year of age. Strong genetic continuity in the development of CC was found, but also new sets of genes were activated during the first year of life. The origin of the environmental part of the variation could be tracked before 3 months of age. A substantial part of common and specific environmental factors affecting CC affected also birthweight. Conclusions:  CC is sensitive to intrauterine environmental factors, but these effects diminish during the first year of life, at least if postnatal environment is good. CC can be a useful indicator when identifying newborns who have suffered suboptimal pre-natal conditions.
    Paediatric and Perinatal Epidemiology 11/2012; 26(6):553-560.
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    ABSTRACT: Eur J Clin Invest 2012 ABSTRACT: Purpose  While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas. Methods  We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken. Results  Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area. Conclusions  The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty.
    European Journal of Clinical Investigation 09/2012;
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