Journal of Molecular Endocrinology (J MOL ENDOCRINOL )

Publisher: Society for Endocrinology, Society for Endocrinology


Journal of Molecular Endocrinology focuses specifically on endocrinology research at the cellular and molecular level, thus complementing Journal of Endocrinology.

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    Journal of Molecular Endocrinology website
  • Other titles
    Journal of molecular endocrinology (Online), JME
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  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

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Society for Endocrinology

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    • Author cannot archive a pre-print version
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    • Author cannot archive a post-print version
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    • 12 months embargo
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    • Publisher copyright and source must be acknowledged
    • Authors accepted manuscript must carry a set statement (see policy)
    • On a non-profit server
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    • For articles post April 2013, please see BioScientifica
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs have been implicated in a variety of physiological processes, however, the function of miRNAs in insulin secretion and type 2 diabetes is still unclear. Stxbp1 plays an essential role in exocytosis, and is crucial for insulin secretion. In this study, we focused on the molecular mechanism of Stxbp1 in insulin secretion by identifying its upstream regulators: miR-218 and miR-322. The Stxbp1 expression was significantly increased in isolated mouse islets exposed to high glucose within 1 hour; while 2 of its predicted upstream miRNAs were found to be down-regulated. Further study found that miR-218 and miR-322 directly interact with Stxbp1 by target the 3'UTR of its mRNA. MIN6 cells overexpressed with the two miRNAs showed a sharp decline in insulin secretion and a decreased sensitivity to glucose; while the inhibition of the two miRNAs promoted insulin secretion. However, islets treated with prolonged high glucose, which is known as glucolipotoxicity, displayed relatively high expression of miR-218 and miR-322, and a reduced level of Stxbp1 accompanied with the block of insulin secretion. In summary, this study identified the pathway consisting of miR-218/322 and Stxbp1 in insulin secretion, contributing to the miRNA-implicated network of beta-cell function.
    Journal of Molecular Endocrinology 12/2014;
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    ABSTRACT: Diabetes can be managed by careful monitoring of blood glucose and timely delivery of exogenous insulin. However, even with fastidious compliance, people with diabetes can suffer from numerous complications including atherosclerosis, retinopathy, neuropathy, and kidney disease. This is because delivery of exogenous insulin coupled with glucose monitoring cannot provide the fine level of glucose control normally provided by endogenous β-cells in the context of intact islets. Moreover, a subset of people with diabetes lack awareness of hypoglycemic events; a status that can have grave consequences. Therefore, much effort has been focused on replacing lost or dysfunctional β-cells with cells derived from other sources. The advent of stem cell biology and cellular reprogramming strategies have provided impetus to this work and raised hopes that a β-cell replacement therapy is on the horizon. In this review, we look at two components that will be required for successful β-cell replacement therapy: a reliable and safe source of β-cells and a mechanism by which such cells can be delivered and protected from host immune destruction. Particular attention is paid to insulin-producing cells derived from pluripotent stem cells because this platform addresses the issue of scale, one of the more significant hurdles associated with potential cell-based therapies. We also review methods for encapsulating transplanted cells, a technique that allows grafts to evade immune attack and survive for a long term in the absence of ongoing immunosuppression. In surveying the literature, we conclude that there are still several substantial hurdles that need to be cleared before a stem cell-based β-cell replacement therapy for diabetes becomes a reality.
    Journal of Molecular Endocrinology 12/2014; 53(3):R119-R129.
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    ABSTRACT: Activation of thyroxine by outer ring deiodination is the crucial first step of thyroid hormone action. Substrate-induced ubiquitination of type 2 deiodinase (D2) is the most rapid and sensitive mechanism known to regulate thyroid hormone activation. While the molecular machinery responsible for D2 ubiquitination has been extensively studied, the combination of molecular features sufficient and required to allow D2 ubiquitination remained to be determined. To address this question we constructed chimeric deiodinases by introducing different combinations of D2-specific elements into type 1 deiodinase (D1), another member of the deiodinase enzyme family, which however does not undergo ubiquitination in its native form. Studies on the chimeric proteins expressed transiently in HEK-293T cells revealed that combined insertion of the D2-specific instability loop and the K237/K244 D2 ubiquitin-carrier lysines into the corresponding positions of D1 could-not ubiquitinate D1 unless the chimera was directed to the endoplasmic reticulum (ER). Fluorescence resonance energy transfer measurements demonstrated that the C-terminal globular domain of the ER-directed chimera was able to interact with the E3 ligase subunit WSB1. However, this interaction did not occur between the chimera and the TEB4 E3 ligase although a native D2 could readily interact with the N-terminus of TEB4. In conclusion, insertion of the instability loop and ubiquitin-carrier lysines in combination with direction to the ER are sufficient and required to govern WSB1-mediated ubiquitination of an activating deiodinase enzyme.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: The proteolysis of the pro-opiomelanocortin precursor results in the formation of melanocortins (MCs), a group of peptides that share the conserved -H-F-R-W- sequence, which acts as a pharmacophore for five subtypes of melanocortin receptors (MCRs). Melanocortin type 2 receptor (MC2R; also known as ACTHR) is the most specialized of all the MCRs. It is predominantly expressed in the adrenal cortex and specifically binds ACTH. Unlike other MCRs, it requires MRAP1 for formation of active receptor and for its transport to the cell membrane. The molecular mechanisms underlying this specificity remain poorly understood. In this study, we used directed mutagenesis to investigate the role of various short MC2R sequence segments on receptor membrane trafficking and specific activation upon stimulation with ligands. The strategy of the study was to replace 2-5 amino acid residues within one MC2R segment with the corresponding residues of MC4R. In total, 20 recombinant receptors C-terminally fused to enhanced green fluorescent protein were generated and their membrane trafficking efficiencies and cAMP response upon stimulation with -MSH and ACTH(1-24) were estimated during their stand-alone expression and co-expression with MRAP1-. Our results indicate that both the motif that determines the ligand-recognition specificity and the intracellular retention signal are formed by a specific extracellular structure, which is supported by the correct alignment of the transmembrane. Our results also suggest that the aromatic-residue-rich segment of extracellular loop 2 is involved in the effects mediated by the second ACTH pharmacophore (-K-K-R-R-).
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: CD163-positive macrophages are highly expressed in the human adipose tissue (AT) particularly from obese individuals. Little is, however, known about the regulation of CD163 mRNA and the protein level of sCD163 in human AT. We aimed to examine the regulation of CD163 and sCD163 in AT. Human subcutaneous AT samples (n=5) were stimulated with dexamethasone (DEX; 200 nmol/L), lipopolysaccharide (LPS; 100 ng/mL), or DEX+LPS for various time periods up to 24 hours. Gene expressions of CD163, ADAM17, IL10, and TNFA were measured by RT-PCR. Protein levels of sCD163, IL-10, and TNF-α were measured by ELISA. Furthermore, AT was separated into the stromal and adipocyte fraction. We found that CD163 mRNA was strongly expressed in the stromal vascular fraction but hardly detectable in the isolated adipocytes. Incubating whole-AT with DEX significantly up-regulated CD163 (p<0.001), whereas, incubation with LPS had no effects on CD163 (p>0.05). In contrast, the protein level of sCD163 was not affected by DEX (p>0.05) but LPS significantly increased the level of sCD163 and TNF-α (p<0.05). This might be due to the concomitant LPS-stimulation of ADAM17, which is known to mediate shedding of the extracellular domains of sCD163 and TNF-α. Finally, DEX significantly reduced the LPS-induced TNF-α release to the incubation medium but had no effects on sCD163. We conclude that the expression of CD163 and the release of sCD163 are differentially regulated in human AT. Moreover, similar to studies on differentiated blood monocytes, TNF-α and sCD163 are concomitantly released in human AT by LPS, which also up-regulate ADAM17.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Despite its identification over 100 years ago, new discoveries continue to add to the complexity of the regulation of the endocrine system. Today the nuclear receptors (NRs) that play such a pivotal role in the extensive communication networks of hormones and gene expression, remain an area of intense research. Orchestrating core processes from metabolism to organismal development, the gene expression programs they control are dependent on their cellular context, their own levels, and those of numerous co-regulatory proteins. A previously unknown component of these networks, non-coding RNAs (ncRNAs) are now recognized as potent regulators of NR signaling, impacting receptor and co-factor levels and function while being reciprocally regulated by the NRs themselves. This review explores the regulation enacted by microRNAs (miRNAs) and long ncRNAs (lncRNAs) on NR function, using representative examples to show the varied impacts of ncRNAs, in turn producing significant effects on the NR functional network in health and disease.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Estrogens are essential for female reproduction and overall well-being, and estrogens in circulation are largely synthesized in ovarian granulosa cells. Using primary culture of ovarian granulosa cells from gonadotropin-primed immature rats, we recently uncovered that pituitary FSH and ovarian cytokine TGFβ1 induce calcineurin-mediated dephosphorylation-activation of CREB-regulated transcription coactivator (CRTC2) to modulate the expression of Star, Cyp11a1 and Hsd3b leading to increased progesterone production. This study explored the role of calcineurin and CRTC2 in FSH and TGFβ1 regulation of Cyp19a1 expression in granulosa cells. Ovarian granulosa cells given FSH had increased aromatase protein at 24 h post-treatment which subsided by 48 h, while TGFβ1 acting through its type I receptor augmented FSH action with a greater and longer effect. It is known that ovary-specific Cyp19a1 PII-promoter contains crucial response elements for CREB and nuclear receptors LRH-1/NR5A2 and SF-1/NR5A1, and Nr5a2 promoter also has a potential CREB-binding site. Here, we demonstrate FSH plus TGFβ1 increased LRH-1 and SF-1 protein, and their binding to Cyp19a1 PII-promoter evidenced by chromatin immunoprecipitation analysis. Moreover, pretreatment with calcineurin auto-inhibitory peptide (CNI) abolished the FSH+TGFβ1- but not FSH-upregulated aromatase activity at 48 h, and the corresponding mRNA changes of Cyp19a1, and Nr5a2 and Nr5a1 at 24 h. Additionally, FSH and TGFβ1 increased CRTC2 binding to Cyp19a1 PII-promoter and Nr5a2 promoter at 24 h with CREB bound constitutively. In all, this study implicates calcineurin and CRTC2 importantly mediate FSH and TGFβ1 collateral upregulation of Cyp19a1 expression together with its transcription regulators Nr5a2 and Nr5a1 in ovarian granulosa cells.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Current view of the control of spermatogenesis by Fsh and Lh in non-mammalian vertebrates is largely based on teleosts with cystic and cyclic spermatogenesis. Much less is known concerning the specific actions of gonadotropins during semicystic germ cell development, a type of spermatogenesis in which germ cells are released into the tubular lumen where they transform into spermatozoa. Here, using homologous gonadotropins and a candidate gene approach, for which their testicular cell type-specific expression was established, we investigated the regulatory pathways of Fsh and Lh on gene expression during Senegalese sole (Solea senegalensis) spermatogenesis, a flatfish with asynchronous and semicystic germ cell development. During early spermatogenesis, Fsh and Lh upregulated steroidogenesis-related genes and nuclear steroid receptors, expressed in both somatic and germ cells, through steroid-dependent pathways, although Lh preferentially stimulated the expression of downstream genes involved in androgen and progestin synthesis. In addition, Lh specifically promoted the expression of spermatid-specific genes encoding spermatozoan flagellar proteins through direct interaction with the Lh receptor in these cells. Interestingly, at this spermatogenic stage, Fsh primarily regulated genes encoding Sertoli cell growth factors with potentially antagonistic effects on germ cell proliferation and differentiation through steroid mediation. During late spermatogenesis, fewer genes were regulated by Fsh or Lh, which was associated with a translational and posttranslational downregulation of the Fsh receptor in different testicular compartments. These data reveal that conserved and specialised gonadotropic pathways regulate semicystic spermatogenesis in flatfish, which may spatially adjust cell germ development to assure a continuous reservoir of spermatids in the testis.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and NRs to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders (CVDs). Pharmacologic interventions targeting the RAS cascade has led to the discovery of renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, and AT1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins or G protein-independently through β-arrestin are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT1 receptor.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Hepatic steatosis is highly correlated with insulin resistance and diabetes. Although it has been shown that activation of free fatty acid receptor 1 (FFAR1) by agonists is beneficial in the treatment of diabetes, the effects of FFAR1 agonists on hepatic steatosis are still unknown. In this study, high fat diet (HFD)-induced hepatic steatosis animal model was utilized to evaluate the effect of FFAR1 agonist, GW9508, on the hepatic lipid accumulation, and HepG2 hepatoma cells was also used to clarify the possible mechanisms. Administration of GW9508 in HFD mice significantly reduced hepatic lipid accumulation through the decreased expressions of lipognesis-related proteins. Knockdown of hepatic FFAR1 by lentiviral vectors containing short hairpin RNA targeted to FFAR1 diminished the effect of GW9508. In addition, GW9508 decreased oleic acid-induced lipid accumulation in HepG2 cells by reducing the expressions of lipogenesis-related proteins. Moreover, GW9508 down-regulated the expression of sterol regulatory element binding protein-1 (SREBP-1) through a p38-dependent pathway, whereas knockdown of FFAR1 in HepG2 cells diminished the effect of GW9508 on the decrease of SREBP-1. Taken together, GW9508 exerts a therapeutic effect to improve hepatic steatosis through a p38-dependent pathway. Thus, investigation of chemicals that act on FFAR1 might be a new strategy for the treatment of hepatic steatosis.
    Journal of Molecular Endocrinology 07/2014;
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    ABSTRACT: Vascular extracellular matrix (ECM) remodelling, which is the result of disruption in the balance of extracellular matrix synthesis and degradation, induces vessel fibrosis and thereby leads to hypertension. Leptin is known to promote tissue fibrosis, while adiponectin has recently been demonstrated to be anti-fibrogenic in tissue fibrosis. Here, we aimed to evaluate the leptin-antagonist function of adiponectin and to further elucidate the mechanisms through which adiponectin dampens leptin signalling in vascular smooth muscle cells, thus preventing excess ECM production in our already established 3D co-culture vessel models. Our 3D vessel model, which mimics true blood vessels, is composed of vascular endothelial cells, vascular smooth muscle cells, and collagen type I. We validated the profibrogenic effects of leptin and analysed MMP-2, MMP-9, TIMP-1, and collagen type II/IV secretion in 3D vessel models. The protective/inhibitory effects of adiponectin were re-analysed by inhibiting adiponectin receptor-1 and receptor-2 expression in endothelial cells using RNAi technology. In the 3D vessel models, adiponectin blocked the leptin-stimulated secretion of collagen types II/IV and TIMP-1 while significantly increasing MMP-2/9 activity. In endothelial cells, adiponectin induced phosphorylation of AMPK, thereby suppressing leptin-mediated Stat3 phosphorylation through SOCS-3 induction in smooth muscle cells. Our findings highlight that adiponectin disrupted the leptin-induced vascular extracellular matrix remodelling via adiponectin receptor-1 and enhanced AMPK signalling in endothelial cells, which, in turn, promoted SOCS-3 up-regulation in smooth muscle cells to repress leptin-stimulated phosphorylation of Stat3.
    Journal of Molecular Endocrinology 06/2014;
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    ABSTRACT: Intrauterine growth restriction (IUGR) is a risk factor for obesity, particularly when offspring are born into an unrestricted nutritional environment. Herein we investigated the impact of IUGR and gender on circulating lipids and on adipogenic, lipogenic and adipokine gene expression in perirenal adipose tissue. Singleton lambs born to overnourished adolescent dams were normal birthweight (N) or IUGR (32% lower birthweight due to placental insufficiency). IUGR lambs exhibited increased fractional growth rates but remained smaller than N at necropsy (d77). At 48d, fasting plasma triglycerides, nonesterified fatty acids and glycerol were elevated predominantly in IUGR males. Body fat content was independent of prenatal growth but higher in females than males. In perirenal fat, relative to male lambs, females had larger adipocytes and lipoprotein lipase, fatty acid synthase and leptin mRNA expression levels were higher while IGF1, IGF2, IGF1R, IGF2R and hormone sensitive lipase mRNAs were lower, and all were independent of prenatal growth category; peroxisome-proliferator-activated receptor-γ and glycerol-3-phosphate dehydrogenase (G3PDH) mRNA expression were not affected by IUGR or gender. Adiposity indices were inversely related to G3PDH mRNA expression, and for the population as a whole the expression of IGF system genes in perirenal fat was negatively correlated with plasma leptin, fat mass and adipocyte size, and positively correlated with circulating IGF1. Higher plasma lipids in IUGR males may predict later adverse metabolic health and obesity, but in early postnatal life gender is the dominant influence on adipose tissue gene expression reflecting the already established sexual dimorphism in body composition.
    Journal of Molecular Endocrinology 06/2014;
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    ABSTRACT: Insect molting and metamorphosis are regulated by two hormones: 20-hydroxyecdysone (20E) and juvenile hormone (JH). 20E regulates gene transcription via nuclear receptor EcR to promote metamorphosis, whereas JH regulates gene transcription via its intracellular receptor methoprene-tolerant (Met) to prevent larval-pupal transition. However, the function and mechanism of Met in various insect developments is not well understood. We propose that Met1 plays a key role in maintaining larval status not only by promoting JH-responsive gene transcription but also by repressing 20E-responsive gene transcription in the Lepidopteran insect Helicoverpa armigera. Met1 protein is increased during feeding stage and decreased during molting and metamorphic stages. Met1 is upregulated by JH III and low concentration of 20E independently, but is downregulated by high concentration of 20E. Knockdown of Met1 in larvae causes precocious pupation, decrease of JH pathway gene expression, and increase of 20E pathway gene expression. Met1 interacts with heat-shock protein 90 and binds to JH response element to regulate Krüppel homolog 1 transcription in JH III induction. Met1 interacts with ultraspiracle protein 1 (USP1) to repress 20E transcription complex EcR-B1/USP1 formation and binding to ecdysone response element. These data indicate that JH via Met1 regulates JH pathway gene expression and represses 20E pathway gene expression to maintain larval status.
    Journal of Molecular Endocrinology 05/2014;
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    ABSTRACT: Abstract Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. However, recent studies also show evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are up-regulated and released into the circulation. The most abundant of these, tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β) and interleukin-6 (IL-6), are all known to directly act on the growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation partly can be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective preventing growth failure in patients with chronic inflammatory disorders. In this review we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.
    Journal of Molecular Endocrinology 04/2014;
  • Journal of Molecular Endocrinology 01/2014; 52(3):269-77.
  • Journal of Molecular Endocrinology 01/2009; 42:269.