The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.

Objectives:\ud The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown.\ud \ud Methods:\ud Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed alo…

Die Messung des freien Speichel-Cortisols vor und nach intravenöser Stimulation mit Corticotropin-Releasing Hormon. Der Einfluß basaler Cortisolspiegel auf die Stimulierbarkeit.

Prädiktive genetische Untersuchungen: Individualisierung von Diagnostik und Therapie bei Familien mit multipler endokriner Neoplasie Typ II

BACKGROUND AND OBJECTIVE When multiple endocrine neoplasia type 2 (MEN2) is suspected, genetic tests are at the centre of screening procedures. It was the aim of this study to compare the diagnostic value of molecular biological investigations with that of conventional biochemical tests. PATIENTS AND METHODS The study cohort consisted of all 144 patients cared for in our department since 1990 with the suspected diagnosis of MEN2 (evidence of a medullary thyroid carcinoma [MTC]), coexistence of two MEN2 tumours or a family history of MEN2. 14 of the 144 patients (from 12 families) were already known to have an hereditary MTC, while the remaining 130 had been referred for further diagnostic i…

Thyrotropin-releasing hormone has stimulatory effects on ventilation in humans

Thyrotropin-releasing hormone (TRH) stimulates pituitary thyrotropin synthesis and release and also regulates autonomic nervous system functions by acting as a neuromodulator and neurotransmitter. In experimental animals a stimulation of ventilation by thyrotropin-releasing hormone was shown when applied at central nervous system sites that affect respiratory motor output. It was the goal of our study to investigate the respiratory properties of thyrotropin-releasing hormone on basal and stimulated (i.e. CO2-rebreathing) conditions following systemic thyrotropin-releasing hormone application in healthy humans. Thyrotropin-releasing hormone (200 micrograms, 400 micrograms intravenous) initia…

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

Contains fulltext : 172720.pdf (Publisher’s version ) (Open Access) Recently, activating mutations of the hypoxia-inducible factor 2alpha gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors o…

Extrapituitary Effects of Corticotropin Releasing Hormone and Thyrotropin Releasing Hormone

Besides their regulation of the pituitary-adrenal and pituitary-thyroidal axis, respectively, the neurohormones CRH and TRH act within the central nervous system to evoke and modulate a number of behavioral and physiological processes. In particular, an increase in the sympathetic nervous system and respiratory activity has been observed. The data communicated in this review article emphasize the role of these neurohormones with regard to the neuroendocrine regulation of the autonomic nervous system, sleep and cognitive performance. Moreover, a possible therapeutic role is suggested by the beneficial effects in patients at risk of hypoventilation-associated disorders.

Intra- and extracerebral blood flow changes and flushing after intravenous injection of human corticotropin-releasing hormone

To study facial flush after systemic administration of human corticotropin-releasing hormone (hCRH) we injected 100 micrograms hCRH intravenously to ten healthy young men. The increase in facial temperature was measured by infrared camera. A significant increase in facial temperature of 1.39 degrees C +/- 0.3 was found within 7 min in all patients, which lasted up to 60 min, although facial flushing was visible in only 50% (5/10) of the probands. In a second experiment 100 micrograms hCRH was then administered to seven other healthy young men. Intra- and extracerebral blood flow velocity changes in the medial cerebral artery (MCA) and external carotid artery (ECA) were measured after hCRH a…

Human corticotropin-releasing hormone and thyrotropin-releasing hormone modulate the hypercapnic ventilatory response in humans

Human corticotropin-releasing hormone (hCRH) and thyrotropin-releasing hormone (TRH) are known to stimulate ventilation after i.v. administration in humans. In a placebo-controlled, single-blind study we aimed to clarify if both peptides act by altering central chemosensitivity. Two subsequent CO2-rebreathing tests were performed in healthy young volunteers. During the first test 0.9% NaCl was given i.v.; during the second test 200 micrograms of hCRH (n = 12) or 400 micrograms of TRH (n = 6) was administered i.v. Nine subjects received 0.9% NaCl i.v. during both rebreathing manoeuvres. The CO2-response curves for the two tests were compared within the same subject. In the hCRH group a marke…

Pavlovian conditioning of corticotropin-releasing factor-induced increase of blood pressure and corticosterone secretion in the rat

Corticotropin-releasing factor (CRF) is clearly involved in the central regulation of the pituitary-adrenal axis and, moreover, of autonomic nervous system functions. Enhanced sympathetic activity with subsequent increases in blood pressure and heart rate and attenuation of the baroreceptor reflex results from the intracerebroventricular (i.c.v.) administration of CRF. Additionally, the peptide has a variety of potent effects on behavioural responses in animals similar to those observed after an experimentally evoked stress. It was therefore of obvious interest to examine whether CRF is a possible mediator of the learning processes associated with physiological stress reaction patterns. Thi…

Cardiovascular and Endocrine Properties of L-Tryptophan in Combination with Various Diets

Brain serotonin neurons are intimately involved in a number of relevant physiological functions such as cardiovascular regulation, neuroendocrine output from the anterior pituitary (e.g. ACTH, prolactin), regulation of behavior (e.g. agression, sleep, locomotor and sexual behavior), mood or appetite control (Fernstrom, 1983; Lehnert et al., 1987; Spring et al., 1987; Wurtman, 1987). The synthesis of brain serotonin is dependent on the availability of the large neutral amino acid L-tryptophan that is hydroxylated to 5-L-hydroxytryptophan and subsequently decarboxylated to yield serotonin. The rate-limiting enzyme tryptophan hydroxylase has a Michaelis constant of approximately 2–3 x 10−5 M w…

Effects of L-tyrosine and L-tryptophan on the cardiovascular and endocrine system in humans

Brain catecholamine and serotonin neurons are intimately involved in a number of relevant physiological functions such as cardiovascular regulation, neuroendocrine output from the anterior pituitary (e.g. ACTH, prolactin), regulation of behavior (e.g. aggression, sleep, locomotor and sexual behavior), mood or appetite control [1–5]. The modification of transmitter synthesis and release appears to be remarkably correlated with the subsequent physiological changes observed. While there are numerous pharmacological approaches that affect the respective neurotransmitter products (i.e. the catecholamines dopamine, noradrenaline and adrenaline and the indoleamine serotonin), one particular attrac…

Zentralnervöse Appetitregulation: Mechanismen und Bedeutung für die Entstehung der Adipositas

This review focuses on neurotransmitter and neuropeptide actions on food ingestion, as well as on some of the mechanisms that may lead to the development and maintenance of obesity. In particular, the role of hypothalamic amines (catecholamines, serotonin) in appetite control is described. Thus, hypothalamic noradrenaline appears to stimulate food intake, while an enhanced brain serotonergic neurotransmission leads to a suppression of food ingestion, preferentially of carbohydrate intake. The involvement of brain serotonin neurons in appetite control is most attractive, since serotonin synthesis and release is readily affected by either precursor loading (i.e., 1-tryptophan) or pharmacologi…

Intraoperative localization of malignant pheochromocytoma by 123-i-metaiodobenzylguanidine single probe measurement

Metaiodobenzylguanidine (MIBG) imaging is a well-established method for locating intra- and extraadrenal pheochromocytomas. We investigated whether preoperative injection of 123-I-MIBG might be useful for intraoperative staging of chromaffine tumor cells. This was performed in a 46-year-old patient in whom the diagnosis of a malignant pheochromocytoma had been established by 123-I-MIBG imaging and enhanced catecholamine secretion. The rationale for intraoperative staging in this patient was a discrepancy between computed tomography (CI) of the abdomen and the radionuclide imaging, because scintigraphy revealed a mass with MIBG uptake in the right lower abdomen that could not be visualized b…

Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.

We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutatio…

The LepR-mediated leptin transport across brain barriers controls food reward

Objective Leptin is a key hormone in the control of appetite and body weight. Predominantly produced by white adipose tissue, it acts on the brain to inhibit homeostatic feeding and food reward. Leptin has free access to circumventricular organs, such as the median eminence, but entry into other brain centers is restricted by the blood–brain and blood–CSF barriers. So far, it is unknown for which of its central effects leptin has to penetrate brain barriers. In addition, the mechanisms mediating the transport across barriers are unclear although high expression in brain barriers suggests an important role of the leptin receptor (LepR). Methods We selectively deleted LepR in brain endothelia…

Control for carbon dioxide-related changes in flow velocity by transcranial Doppler monitoring.

Transcranial Doppler ultrasonography can monitor changes in intracranial blood flow velocity over time in a variety of experimental and clinical settings with excellent temporal resolution. Alterations in arterial carbon dioxide pressure exert a profound influence on blood flow velocity. Such changes exhibit important individual fluctuation depending on respiratory status. This limits the ability of transcranial Doppler to accurately study subtle changes in blood flow velocity, independent of the respiratory state of the subject. Suggested here is a method to control for the respiration artifact on blood flow velocity. The middle cerebral artery of 7 healthy male volunteers was studied with…

Respiratory Parameters after Systemic Corticotropin-Releasing Hormone Administration

Neuroanatomical studies on the distribution of corticotropin-releasing hormone (CRH) and its receptors (7) as well as physiological data suggest a regulatory function of endogenous CRH in hypothalamic and extrahypothalamic brain areas [1, 4]. Endogenous CRH acts within the endocrine hypothalamo-pituitary-adrenal axis and affects cardiovascular regulation and respiration through extrahypothalamic pathways. CRH also stimulates gluconeogenesis and release of plasma-catecholamines. Our experiments in humans also demonstrate an influence on respiration and on heart rate activity after systemic application of CRH. Respiratory parameters and heart rate were analyzed during steady-state conditions …

Safety and side effects of human and ovine corticotropin-releasing hormone administration in man.

Synthetic human and ovine corticotropin-releasing hormone (hCRH, oCRH) are commonly used as a diagnostic tool of the hypothalamo-pituitary-adrenal axis. In this paper reports about side effects after various modes of CRH-application are analyzed and compared to our corresponding data of human studies with hCRH and oCRH. Generally, CRH is well tolerated after single administration and interval-application of standard doses, although minor side effects appear sometimes after higher doses (greater than 200 micrograms hCRH, oCRH) of CRH-bolus-injections. Predominantly the cardiovascular system (e.g. tachycardia, hypotension, flushing) is affected; neuropsychological symptoms are only seen spora…

Effects of corticotropin-releasing hormone on respiratory parameters during sleep in normal men.

Corticotropin-releasing hormone (CRH) is well-known to be a centrally acting respiratory stimulant after systemic application both in healthy subjects and in patients suffering from respiratory failure. In order to study the effects of CRH on sleep EEG and respiratory parameters during sleep, 14 healthy male volunteers were investigated in a single-blind placebo controlled design. After an adaptation night, polysomnography was performed during two successive nights between 23.00 hrs. and 7.00 hrs. During one night placebo was applied, on the other 50 μg ovine CRH was administered intravenously as a bolus every hour from 0.00 hrs. to 6.00 hrs. For the assessment of respiration, blood oxygen …

Treatment of Severe Reactive Hypoglycemia With a Somatostatin Analogue (SMS 201-995)

• Reactive (or postprandial) hypoglycemia can sometimes represent a severe disorder refractory to conventional therapeutic measures. We present in this first individual trial, to our knowledge, that the administration of a somatostatin analogue (SMS 201 -995) may alleviate the severity of complaints and does not appear to be diabetogenic. The effects of the somatostatin analogue were documented in a 5-hour oral glucose tolerance test, where not only the glucose-induced and C-peptide rise was clearly attenuated, but also the blood glucose concentration did not fall low enough to induce hypoglycemic symptoms. ( Arch Intern Med. 1990;150:2401-2402)