The incretin hormone glucagon-like peptide-1 (GLP-1) binds to and activates its G-protein-coupled-receptor GLP-1R to reduce glycaemia through the stimulation of insulin and suppression of pancreatic ...glucagon secretion. Recently, GLP-1 effects unrelated to glucose homeostasis have been discovered in myocardium, bone, adipose tissue, and other target organs, which appear to be mainly mediated by GLP-1R-independent pathways. Here, we summarize knowledge on GLP-1R agonists (GLP-1RAs) as they relate to the improvement of glucose control, and focus on the most recently described effects, discussing the preclinical evidence of the involvement of alternative receptors and signalling mechanisms. It is now evident that the universe of GLP-1RAs is expanding further from the initial incretin effect, opening new unforeseen avenues for research and clinical applications.
Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men ...generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels.
Meta-analysis.
An extensive Medline search was performed including the following words: 'testosterone', 'diet', 'weight loss', 'bariatric surgery', and 'males'. The search was restricted to data from January 1, 1969 up to August 31, 2012.
Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery. Overall, both a low-calorie diet and bariatric surgery are associated with a significant (P<0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51-10.95) vs 2.87 (1.68-4.07) for bariatric surgery and the low-calorie diet, respectively; both P<0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B=2.50±0.98, P=0.029).
These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.
Abstract
Context
Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure.
Objective
To investigate the relationship between transcriptome profile and ...genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms.
Design
Cross-sectional study.
Setting
University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT).
Patients
We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma CPA), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs).
Intervention
Ribonucleic acid (RNA) sequencing.
Main Outcome Measures
Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing.
Results
Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation.
Conclusions
MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.
Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome from murine colon carcinoma CT26 ...induces cachectic features in both murine and human adipocytes that are associated with metabolic alterations such as enhanced lactate production and decreased oxygen consumption. The use of oxamate, which inhibits lactate dehydrogenase activity, hinders the effects induced by CT26 secretome. Interestingly, the CT26 secretome elicits an increased level of lactate dehydrogenase and decreased expression of adiponectin. These modifications are driven by the STAT3 signalling cascade since the inhibition of STAT3 with WP1066 impedes the formation of the cachectic condition and the alteration of lactate dehydrogenase and adiponectin levels. Collectively, these findings show that STAT3 is responsible for the altered lactate dehydrogenase and adiponectin levels that, in turn, could participate in the worsening of this pathology and highlight a step forward in the comprehension of the mechanisms underlying the onset of the cachectic condition in adipocytes.
The rapid effects of steroids on spermatozoa have been demonstrated for the first time two decades ago. Progesterone (P), which is present throughout the female genital tract with peaks of levels in ...the cumulus matrix surrounding the oocyte, stimulates several sperm functions, including hyperactivation and acrosome reaction. These effects are mediated by an extranuclear pathway, as P stimulates an influx of calcium, the tyrosine phosphorylation of sperm proteins and other signalling cascades in a rapid manner. Whether these effects are receptor mediated and which receptors mediate these effects are still a matter of discussion despite all the efforts of the scientific community aimed at identifying them during the last 20 years. Although responsiveness to P is related to sperm fertilizing ability, the physiological role of P during the process of fertilization is discussed, and recent evidence points for a role of the steroid as a chemotactic agent for sperm. A similar situation applies for estrogens (E), which have been shown to induce direct effects on sperm by an extranuclear pathway. In particular, E appear to decrease acrosome reaction in response to P, exerting a role in ensuring an appropriate timing for sperm exocytosis during the process of fertilization.
Metabolic pathologies mainly originate from adipose tissue (AT) dysfunctions. AT differences are associated with fat-depot anatomic distribution in subcutaneous (SAT) and visceral omental (VAT) pads. ...We address the question whether the functional differences between the two compartments may be present early in the adipose stem cell (ASC) instead of being restricted to the mature adipocytes. Using a specific human ASC model, we evaluated proliferation/differentiation of ASC from abdominal SAT-(S-ASC) and VAT-(V-ASC) paired biopsies in parallel as well as the electrophysiological properties and functional activity of ASC and their in vitro-derived adipocytes. A dramatic difference in proliferation and adipogenic potential was observed between the two ASC populations, S-ASC having a growth rate and adipogenic potential significantly higher than V-ASC and giving rise to more functional and better organized adipocytes. To our knowledge, this is the first comprehensive electrophysiological analysis of ASC and derived-adipocytes, showing electrophysiological properties, such as membrane potential, capacitance and K(+)-current parameters which confirm the better functionality of S-ASC and their derived adipocytes. We document the greater ability of S-ASC-derived adipocytes to secrete adiponectin and their reduced susceptibility to lipolysis. These features may account for the metabolic differences observed between the SAT and VAT. Our findings suggest that VAT and SAT functional differences originate at the level of the adult ASC which maintains a memory of its fat pad of origin. Such stem cell differences may account for differential adipose depot susceptibility to the development of metabolic dysfunction and may represent a suitable target for specific therapeutic approaches.
The crosstalk between the chromaffin and adrenocortical cells is essential for the endocrine activity of the adrenal glands. This interaction is also likely important for tumorigenesis and ...progression of adrenocortical cancer and pheochromocytoma. We developed a unique in vitro 3D model of the whole adrenal gland called Adrenoid consisting in adrenocortical carcinoma H295R and pheochromocytoma MTT cell lines. Adrenoids showed a round compact morphology with a growth rate significantly higher compared to MTT-spheroids. Confocal analysis of differential fluorescence staining of H295R and MTT cells demonstrated that H295R organized into small clusters inside Adrenoids dispersed in a core of MTT cells. Transmission electron microscopy confirmed the strict cell-cell interaction occurring between H295R and MTT cells in Adrenoids, which displayed ultrastructural features of more functional cells compared to the single cell type monolayer cultures. Adrenoid maintenance of the dual endocrine activity was demonstrated by the expression not only of cortical and chromaffin markers (steroidogenic factor 1, and chromogranin) but also by protein detection of the main enzymes involved in steroidogenesis (steroidogenic acute regulatory protein, and CYP11B1) and in catecholamine production (tyrosine hydroxylase and phenylethanolamine N-methyltransferase). Mass spectrometry detection of steroid hormones and liquid chromatography measurement of catecholamines confirmed Adrenoid functional activity. In conclusion, Adrenoids represent an innovative in vitro 3D-model that mimics the spatial and functional complexity of the adrenal gland, thus being a useful tool to investigate the crosstalk between the two endocrine components in the pathophysiology of this endocrine organ.
In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate ...that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC.
Rapid spatio-temporal organized intracellular signaling is a pivotal mechanism for regulation of functions in many cells, in particular in the female and male gametes, in which functional regulation ...through rapid increases in protein content is not possible since the mechanisms of transcription/translation are somehow frozen due to meiosis block or DNA condensation respectively. A kinase-anchoring proteins (AKAPs) represent a functional conserved family of signal-organizing scaffolding proteins, which due to the specific subcellular distribution and focally compartmentalized cyclic-AMP-dependent protein kinase (PKA) and other enzymes, assuring the coordination of cAMP-responsive events and their integration with other intracellular signals. This review summarizes the actual knowledge on AKAP structure and functions, taking into particular account the role of different AKAPs in regulating reproductive functions such as gametogenesis. Evidence for sperm specific AKAP isoforms and their initiated signaling cascades in mature sperm and the role of this focally activated super-molecular signaling complex in motility are discussed in details with particular emphasis on putative relations between AKAP structural and functional alterations and defects in sperm motility.
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear hormone receptor superfamily of transcription factors, widely expressed in the organism, including adipose, vascular ...and immune cells. Besides the well-known role in lipid/glycidic homeostasis, PPARγ has also recently emerged as a key regulator of inflammatory and immune responses. Besides the natural ligands, more potent synthetic agonists of PPARγ have been developed, including thiazolidinediones (TZDs), currently used in type 2 diabetes treatment, which also exert anti-inflammatory and anti-neoplastic effects. PPARγ mechanism of action has focused considerable attention over the years. This receptor was initially shown to act on gene expression through a direct transcription and an indirect transrepression activity, mainly associated with metabolic and anti-inflammatory effects. Different post-translational modifications of the receptor can modulate PPARγ activity. More recently, rapid nongenomic activity of TZDs affecting post-translation modifications of extranuclear proteins involved in cell signaling, has been reported. In particular, PPARγ can physically interact with protein kinases resulting in a compartment specific recruitment and activity modulation of these enzymes. Among them, ERK can be positively/negatively regulated by PPARγ ligands, as in endothelial cells, where TZDs exert anti-inflammatory effects through a novel mechanism involving a rapid inhibition of ERK1/2 phosphorylation/activation. Finally, some of the TZD anti-tumor effects seem to be PPARγ-independent, raising the possibility that alternative receptors can act through extranuclear nongenomic pathways.
In conclusion, different mechanisms of action of PPARγ seem to coexist in an interacting functional network in the cell, concurring in mediating both pharmacological and natural ligand effects.
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