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- Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. [REVIEW]
- Nat Rev Endocrinol 2014 Nov 11.
Paragangliomas and phaeochromocytomas are neuroendocrine tumours whose pathogenesis and progression are very strongly influenced by genetics. A germline mutation in one of the susceptibility genes identified so far explains ∼40% of all cases; the remaining 60% are thought to be sporadic cases. At least one-third of these sporadic tumours contain a somatic mutation in a predisposing gene. Genetic testing, which is indicated in every patient, is guided by the clinical presentation as well as by the secretory phenotype and the immunohistochemical characterization of the tumours. The diagnosis of an inherited form drives clinical management and tumour surveillance. Different 'omics' profiling methods have provided a neat classification of these tumours in accordance with their genetic background. Transcriptomic studies have identified two main molecular pathways that underlie development of these tumours, one in which the hypoxic pathway is activated (cluster 1) and another in which the MAPK and mTOR (mammalian target of rapamycin) signalling pathways are activated (cluster 2). DNA methylation profiling has uncovered a hypermethylator phenotype in tumours related to SDHx genes (a group of genes comprising SDHA, SDHB, SDHC, SDHD and SDHAF2) and revealed that succinate acts as an oncometabolite, inhibiting 2-oxoglutarate-dependent dioxygenases, such as hypoxia-inducible factor prolyl-hydroxylases and histone and DNA demethylases. 'Omics' data have suggested new therapeutic targets for patients with a malignant tumour. In the near future, new 'omics'-based tests are likely to be transferred into clinical practice with the goal of establishing personalized medical management for affected patients.
- Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 7.:en20141675.
Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract (NTS) where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, NTS, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate although a few key species differences were identified including the amygdala where GLP-1R expression is much higher in primate than in rodent.
- Role of Retinoic Acid and Platelet-Derived Growth Factor Receptor crosstalk in the regulation of neonatal gonocyte and embryonal carcinoma cell differentiation. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 7.:en20141524.
Neonatal gonocytes are direct precursors of spermatogonial stem cells, the cell pool that supports spermatogenesis. Although unipotent in vivo, gonocytes express pluripotency genes common with embryonic stem cells. Previously, we found that all-trans retinoic acid (RA) induced the expression of differentiation markers and a truncated form of PDGFRβ in rat gonocytes, as well as in F9 mouse embryonal carcinoma cells, an embryonic stem cell-surrogate that expresses somatic lineage markers in response to RA. The present study is focused on identifying the signaling pathways involved in RA-induced gonocyte and F9 cell differentiation. MEK1/2 activation was required during F9 cell differentiation towards somatic lineage, whereas its inhibition potentiated RA-induced Stra8 expression, suggesting that MEK1/2 acts as a lineage specification switch in F9 cells. In both cell types, RA increased the expression of the spermatogonial/pre-meiotic marker Stra8, which is in line with F9 cells being at a stage prior to somatic-germline lineage specification. Inhibiting PDGFR kinase activity reduced RA-induced Stra8 expression. Interestingly, RA increased the expression of PDGFRα variant forms in both cell types. Together, these results suggest a potential crosstalk between RA and PDGFR signaling pathways in cell differentiation. RARα inhibition partially reduced RA effects on Stra8 in gonocytes, indicating that RA acts in part via RARα. RA-induced gonocyte differentiation was significantly reduced by inhibiting SRC and JAK2/STAT5 activities, implying that these signaling molecules play a role in gonocyte differentiation. These results suggest that gonocyte and F9 cell differentiation is regulated via crosstalk between RA and PDGFRs using different downstream pathways.
- ErbB receptor-driven prolactinomas respond to targeted lapatinib treatment in female transgenic mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141627.
As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on PRL production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and western blotting analysis confirmed lactotroph-restricted PRL and EGFR or HER2 co-expression. Serum prolactin (PRLlevels in EGFR and HER2 transgenic mice were increased 5- and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor (TKI) for both EGFR and HER2, suppressed serum PRL by 72 and attenuated tumor PRL expression by 80 %, and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis, and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas.
- TLR4 expression in bone marrow-derived cells is both necessary and sufficient to produce the insulin resistance phenotype in diet-induced obesity. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141552.
The anomalous activation of toll-like receptor 4 (TLR4) by dietary fats is one of the most important mechanisms linking obesity to insulin resistance. TLR4 is expressed in most tissues of the body, but its activity in cells of the immune system is expected to underlie its most important roles of inducing inflammation and insulin resistance. Here, we explore the hypothesis that TLR4 expression in bone marrow-derived cells mediates most of the actions of this receptor as an inducer of insulin resistance. Wild type and TLR4-mutant mice were employed in bone marrow transplant experiments producing chimeras that harbored the functional receptor in all cells of the body except bone marrow-derived cells or only in bone marrow-derived cells. Transplanted mice were fed chow or a high-fat diet, and glucose homeostasis was evaluated by glucose and insulin tolerance tests. Insulin signal transduction and the expression of markers of inflammation were evaluated in the liver and white adipose tissue. In addition, we performed liver histology and evaluated the expression of gluconeogenic enzymes. The expression of TLR4 in bone marrow-derived cells only, but not in non-bone-marrow-derived tissues only, was a determining factor in the induction of diet-induced insulin resistance, which was accompanied by increased expression of inflammatory markers in both white adipose tissue and liver as well as increased liver steatosis and increased expression of gluconeogenic enzymes. TLR4 expressed in bone marrow-derived cells is an important mediator of obesity-associated insulin resistance in mice.
- Anogenital distance (AGD) plasticity in adulthood: Implications for its use as a biomarker of fetal androgen action. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141534.
Androgen action during the fetal masculinization-programming window (MPW) determines the maximum potential for growth of androgen-dependent organs (e.g. seminal vesicles, prostate, penis, perineum) and is reflected in anogenital distance (AGD). As such, determining AGD in postnatal life has potential as a lifelong easily accessible biomarker of overall androgen action during the MPW. However, whether the perineum remains androgen-responsive in adulthood and thus responds plastically to perturbed androgen drive remains unexplored. To determine this, we treated adult male rats with either the anti-androgen Flutamide, or the estrogen Diethylstilbestrol (DES) for five weeks, followed by a four-week wash-out period of no treatment. We determined AGD, and its correlate anogenital index (AGI; AGD relative to bodyweight), at weekly intervals across this period and compared this to normal adult rats (male and female), castrated male rats, and appropriate vehicle controls. These data showed that, in addition to reducing circulating testosterone and seminal vesicle weight, castration significantly reduced AGD (by ∼17), demonstrating that there is a degree of plasticity in AGD in adulthood. Flutamide treatment increased circulating testosterone yet also reduced seminal vesicle weight due to local antagonism of androgen receptor. Despite this suppression, surprisingly, Flutamide treatment had no effect on AGD at any time-point. In contrast, whilst DES treatment suppressed circulating testosterone and reduced seminal vesicle weight, it also induced a significant reduction in AGD (by ∼11%), which returned to normal one week after cessation of DES treatment. We conclude that AGD in adult rats exhibits a degree of plasticity, which may be mediated by modulating local androgen/estrogen action. The implications of these findings regarding the use of AGD as a life-long clinical biomarker of fetal androgen action are discussed.
- Mitochondria-associated membrane formation in hormone-stimulated Leydig cell steroidogenesis: Role of ATAD3. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141503.
Leydig cell steroidogenesis is a multi-step process that takes place in the mitochondria and endoplasmic reticulum (ER). The physical association between these two organelles could facilitate both steroidogenesis substrate availability and mitochondrial product passage to steroidogenic enzymes in the ER, thus regulating the rate of steroid formation. Confocal microscopy, using antisera against organelle-specific antigens, and electron microscopy studies demonstrated that there is an increase in the number of mitochondria-ER contact sites in response to hormone treatment in MA-10 mouse tumor Leydig cells. Electron tomography and 3D reconstruction allowed for the visualization of mitochondria-associated membranes (MAMs). MAMs were isolated and found to contain the 67-kDa long isoform of the adenosine triphosphatase (ATPase) family, AAA domain-containing protein 3 (ATAD3). The 67-kDa ATAD3 is anchored in the inner mitochondrial membrane and is enriched in outer-inner mitochondrial membrane contact sites. ATAD3-depleted MA-10 cells showed reduced production of steroids in response to hCG, but not to 22R-hydroxycholesterol treatment, indicating a role of ATAD3 in the delivery of the substrate cholesterol into the mitochondria. The N-terminus of ATAD3 contains 50 amino acids that have been proposed to insert into the outer mitochondrial membrane and associated organelles, such as the ER. Deletion of the ATAD3 N-terminus resulted in the reduction of hormone-stimulated progesterone biosynthesis, suggesting a role of ATAD3 in mitochondria-ER contact site formation. Taken together, these results demonstrate that the hormone-induced, ATAD3-mediated, MAM formation participates in the optimal transfer of cholesterol from the ER into mitochondria for steroidogenesis.
- AGEs-RAGE System Downregulates Sirt1 Through the Ubiquitin-Proteasome Pathway to Promote FN and TGF-β1 Expression in Male Rat Glomerular Mesangial Cells. [JOURNAL ARTICLE]
- Endocrinology 2014 Nov 6.:en20141381.
We previously demonstrated that advanced glycation-end products (AGEs) promote the pathological progression of diabetic nephropathy by decreasing Sirt1 expression in glomerular mesangial cells (GMCs). Here we investigated whether AGEs-RAGE system downregulated Sirt1 expression through ubiquitin-proteasome pathway and whether Sirt1 ubiquitination affected fibronectin (FN) and transforming growth factor (TGF)-β1-two fibrotic indicators in GMCs. Sirt1 was polyubiquitinated and subsequently degraded by proteasome. AGEs increased Sirt1 ubiquitination and proteasome-mediated degradation, shortened Sirt1 half-life, and promoted FN and TGF-β1 expression. Ubiquitin-specific protease 22 (USP22) reduced Sirt1 ubiquitination and degradation and decreased FN and TGF-β1 expression in GMCs under both basal and AGEs-treated conditions. USP22 depletion enhanced Sirt1 degradation and displayed combined effects with AGEs to further promote FN and TGF-β1 expression. RAGE functioned crucial mediating roles in these processes via its C-terminal cytosolic domain. Inhibiting Sirt1 by EX-527 substantially suppressed the downregulation of FN and TGF-β1 resulting from USP22 overexpression under both normal and AGEs-treated conditions, eventually leading to their upregulation in GMCs. These results indicated that the AGEs-RAGE system increased the ubiquitination and subsequent proteasome-mediated degradation of Sirt1 by reducing USP22 level, and AGEs-RAGE-USP22-Sirt1 formed a cascade pathway that regulated FN and TGF-β1 level, which participated in the pathological progression of diabetic nephropathy.
- Obesity: Obesity turns the hepatic epigenetic clock forward. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Nov 4.
- Biology of upper-body and lower-body adipose tissue-link to whole-body phenotypes. [REVIEW]
- Nat Rev Endocrinol 2014 Nov 4.
The distribution of adipose tissue in the body has wide-ranging and reproducible associations with health and disease. Accumulation of adipose tissue in the upper body (abdominal obesity) is associated with the development of cardiovascular disease, insulin resistance, type 2 diabetes mellitus and even all-cause mortality. Conversely, accumulation of fat in the lower body (gluteofemoral obesity) shows opposite associations with cardiovascular disease and type 2 diabetes mellitus when adjusted for overall fat mass. The abdominal depots are characterized by rapid uptake of predominantly diet-derived fat and a high lipid turnover that is easily stimulated by adrenergic receptor activation. The lower-body fat stores have a reduced lipid turnover with a capacity to accommodate fat undergoing redistribution. Lower-body adipose tissue also seems to retain the capacity to recruit additional adipocytes as a result of weight gain and demonstrates fewer signs of inflammatory insult. New data suggest that the profound functional differences between the upper-body and lower-body tissues are controlled by site-specific sets of developmental genes, such as HOXA6, HOXA5, HOXA3, IRX2 and TBX5 in subcutaneous abdominal adipose tissue and HOTAIR, SHOX2 and HOXC11 in gluteofemoral adipose tissue, which are under epigenetic control. This Review discusses the developmental and functional differences between upper-body and lower-body fat depots and provides mechanistic insight into the disease-protective effects of lower-body fat.