Therapeutic perspectives of adipocytokines.

Various adipocyte-secreted factors have been described which profoundly affect insulin sensitivity and might potentially link obesity, insulin resistance and cardiovascular disease. Among those, adiponectin, visfatin and omentin appear as insulin-sensitising adipocytokines, whereas TNF-alpha, IL-6 and resistin induce insulin resistance. Moreover, leptin is a fat-derived key regulator of appetite and energy expenditure.

Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes.

Recently, visfatin was characterized as a novel adipo-cytokine that is upregulated in obesity and exerts insulin-mimetic effects in various tissues. To clarify expression and regulation of this adipocytokine, visfatin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction in 3T3-L1 adipocytes during adipogenesis and after treatment with various hormones known to alter insulin sensitivity. Visfatin expression was about 6-fold higher in 3T3-L1 adipocytes in vitro as compared with epididymal fat in vivo and increased during adipogenic conversion more than 3-fold.

Interleukin-6 is a negative regulator of visfatin gene expression in 3T3-L1 adipocytes.

Visfatin is a novel adipocytokine exerting insulin-mimetic effects in various insulin-sensitive tissues such as liver, muscle, and fat. In contrast, interleukin (IL)-6 is a proinflammatory adipose-secreted factor that induces insulin resistance and plasma concentrations that correlate with the development of type 2 diabetes mellitus. In the present study, the impact of IL-6 on visfatin gene expression in 3T3-L1 adipocytes was determined by quantitative real-time reverse transcription-polymerase chain reaction.

Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours.

Objective: We evaluated three markers (insulin-like growth factor II (IGF-II), cyclooxygenase-2 (COX-2) and ets-1) of thyroid growth stimulation and cell transformation together with a thyroid-specific marker (thyroglobulin (Tg)) for their potential to differentiate benign and malignant follicular thyroid neoplasia (FN).

Design And Methods: mRNA expression levels were determined by real-time PCR in 100 snap-frozen thyroid samples: 36 benign thyroid nodules with different histology and function (19 cold (CTN) and 17 toxic thyroid nodules (TTN)), 36 corresponding normal thyroid tissues of the same patients, eight Graves' disease (GD) thyroids, 10 follicular thyroid carcinomas (FTC) and 10 papillary thyroid carcinomas (PTC).

Results: Mean IGF-II and COX-2 levels were not significantly altered between benign and malignant thyroid nodules (IGF-II) or nodular (FTC, TTN, CTN) and normal thyroid tissues (COX-2).

Two novel mutations in the sixth transmembrane segment of the thyrotropin receptor gene causing hyperfunctioning thyroid nodules.

Autonomously functioning thyroid nodules (AFTNs) can present as hyperfunctioning adenomas or toxic multinodular goiters. In the last decade, a large number of activating mutations have been identified in the thyrotropin receptor (TSHR) gene in autonomously functioning thyroid nodules. Most have been situated close to, or within the sixth transmembrane segment and third intracellular loop of the TSHR where the receptor interacts with the Gs protein.

Iodine nutrition, nodular thyroid disease, and urinary iodine excretion in a German university study population.

We determined the influence of different nutritional factors on the urinary iodine excretion in an East German university population. First, we assessed iodine excretion in spot urine samples. Second, we measured iodine content in the university canteen meals, where approximately 20% of the probands had regular meals.

[Structure of an interdisciplinary pituitary outpatient care unit at the University Hospital of Leipzig and results for treatment of prolactin and growth hormone secreting pituitary tumors].

Background: Treatment of patients with pituitary adenomas is complex and involves several medical specialties. At the Medical Center of the University of Leipzig, Germany, an interdisciplinary pituitary outpatient care unit has been established for 6 years.

Methods: The interdisciplinary collaboration and the outcome of patients with growth hormone-(GH-) and prolactin-secreting pituitary adenomas are described.

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation.

Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD.

[Diagnosis and therapy of thyroid nodules].

Thyroid nodules and goitre can be diagnosed in up to 50% in populations living in iodine deficiency areas. Because of the necessity to exclude malignancy they therefore represent a significant diagnostic and economic problem. Sonography as well as TSH determination are the basic constituents of any thyroid diagnostic work up.

Questionnaire on management of nodular thyroid disease (Annual Meeting of the Thyroid Section of the German Society of Endocrinology 2003).

Nodular thyroid disease is highly prevalent in iodine deficient areas. In Germany it affects approximately 30 % of the adult population. Differential diagnosis of thyroid nodules is directed at exclusion of rare thyroid malignancy and assessment of the nodules' functional characteristics in order to determine the best treatment approach.

Decreased expression of G-protein coupled receptor kinase 2 in cold thyroid nodules.

G-protein coupled receptor kinases (GRKs) have been shown to regulate the homologous desensitization of different G-protein coupled receptors. We have previously demonstrated that the expression of GRK 3 and 4 is increased in hyperfunctioning thyroid nodules (HTNs) and that GRKs 2, 3, 5 and 6 are able to desensitize the TSHR in vitro. Since cold thyroid nodules (CTNs) and HTNs show different molecular and functional properties, different expression patterns of GRKs in these nodules can be expected.

Regulation of adiponectin receptor R1 and R2 gene expression in adipocytes of C57BL/6 mice.

Adiponectin has gained significant attention as a mediator of insulin sensitivity. Recently, two receptors of this adipocyte-secreted hormone, adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2), have been cloned. To improve our understanding of the regulation of these receptors in adipocytes, AdipoR1 and AdipoR2 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction in brown adipocytes and adipocytes from epigonadal and subcutaneous adipose tissue of C57BL/6 mice as a function of feeding and circadian clocks.

Does tumor heterogeneity limit the use of the Weiss criteria in the evaluation of adrenocortical tumors?

Adrenal incidentalomas are detected more frequently with high-resolution imaging modalities. It is difficult to distinguish between benign and malignant lesions despite the so-called histologic Weiss criteria, imaging features, and molecular studies. We here present a 52 yr-old man who was found to have an adrenal incidentaloma during an annual check-up at his urologist.

Expression of regulators of g protein signaling mRNA is differentially regulated in hot and cold thyroid nodules.

Because of their regulatory properties on cellular proliferation and differentiation, regulators of G protein signaling (RGS) have been suggested as potential tumor suppressors. The aim of this study was to describe the normal pattern of RGS transcripts in the thyroid gland systematically and to elucidate their potential role in common thyroid pathologies. Real-time polymerase chain reaction (PCR) was applied to quantify mRNA expression of RGS transcripts in 10 hot thyroid nodules (HTN), 10 cold thyroid nodules (CTN), and corresponding surrounding tissues (ST).

Molecular pathogenesis of euthyroid and toxic multinodular goiter.

The purpose of this review is to summarize current knowledge of the etiology of euthyroid and toxic multinodular goiter (MNG) with respect to the epidemiology, clinical characteristics, and molecular pathology. In reconstructing the line of events from early thyroid hyperplasia to MNG we will argue the predominant neoplastic character of nodular structures, the nature of known somatic mutations, and the importance of mutagenesis. Furthermore, we outline direct and indirect consequences of these somatic mutations for thyroid pathophysiology and summarize information concerning a possible genetic background of euthyroid goiter.

Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes.

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis.

Adiponectin, obesity, and cardiovascular disease.

Several adipocyte-secreted factors have been demonstrated to potentially link obesity, insulin resistance, and cardiovascular disease. Among those, adiponectin is an insulin-sensitizing and anti-inflammatory adipokine, concentrations of which are decreased in obesity-associated metabolic and vascular disorders. Recently, two adiponectin receptors (AdipoR) have been isolated and adenosine monophosphate kinase (AMPK), as well as acetyl coenzyme A carboxylase (ACC), appear to be critical downstream mediators for various effects of this adipokine.

Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules.

In contrast to the molecular etiology of autonomously functioning thyroid nodules, the molecular cause of cold thyroid nodules (CTNs), their benign, functional inactive counterparts, are so far largely unknown. Because of the partially dedifferentiated phenotype of CTNs, alterations in signaling cascades that favor proliferation, but not differentiation, are likely candidates for tumor induction and progression. The importance of RAS mutations for the development of benign nodules with follicular histology is still in question.

Quantitative proteome analysis in benign thyroid nodular disease using the fluorescent ruthenium II tris(bathophenanthroline disulfonate) stain.

Thyroid tumorigenesis involves qualitative and quantitative changes in protein expression, which can be comprehensively studied by proteome analysis. However, one of the technical bottlenecks of proteomics remains a reliable, sensitive and inexpensive method for quantification of differentially expressed proteins. This is due to the limited linear range of most available protein stains, i.

Structural determinants for g protein activation and selectivity in the second intracellular loop of the thyrotropin receptor.

The TSH receptor (TSHR) activates mainly two signal transduction pathways, cAMP production and phosphoinositide turnover, mediated by Gs and Gq coupling, respectively. Several activating deletion and point mutations within intracellular loop 3 (ICL3) and the adjacent portion of transmembrane domain 6 (TM6) support a direct G protein activation by this receptor domain. The ICL3, however, is predicted by modeling to interact with other receptor domains, primarily ICL2, to form a pocket for G protein binding and to allow optimum interaction.

[Molecular aetiology of nodular goitre -- consequences for therapy?].

Up to 15 % of the adult German population display an enlarged thyroid gland and up to 30 % present thyroid nodules. Iodine deficiency is the most important factor in the etiology of nodular goiter. Insulin-like growth factor-I is overexpressed in thyroids in severely iodine deficient areas.

RGS 2 expression is regulated by TSH and inhibits TSH receptor signaling.

Objective: A new family of guanosine triphosphatase-activating proteins known as regulators of G protein signaling (RGS) has been found to regulate the desensitization of several G protein-coupled ligand-induced processes. The expression of nine RGS mRNAs was found in human thyroid tissue (RGS 2, 3, 5, 6, 9, 10, 12, 14 and 16). At present, little is known as to whether any of the RGS proteins play a role in TSH signaling.