| 1. |
- Abadpour, Shadab, et al.
(författare)
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Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT
- 2018
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041 .- 1479-6813. ; 60:3, s. 171-183
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found up-regulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20mM glucose) + LIGHT in vitro and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by up-regulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.
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| 2. |
- Cardoso, Joao C. R., et al.
(författare)
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Corticotropin-releasing hormone family evolution : five ancestral genes remain in some lineages
- 2016
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041 .- 1479-6813. ; 57:1, s. 73-86
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of the peptide family consisting of corticotropin-releasing hormone ( CRH) and the three urocortins ( UCN1-3) has been puzzling due to uneven evolutionary rates. Distinct gene duplication scenarios have been proposed in relation to the two basal rounds of vertebrate genome doubling ( 2R) and the teleost fish-specific genome doubling ( 3R). By analyses of sequences and chromosomal regions, including many neighboring gene families, we show here that the vertebrate progenitor had two peptide genes that served as the founders of separate subfamilies. Then, 2R resulted in a total of five members: one subfamily consists of CRH1, CRH2, and UCN1. The other subfamily contains UCN2 and UCN3. All five peptide genes are present in the slowly evolving genomes of the coelacanth Latimeria chalumnae ( a lobe-finned fish), the spotted gar Lepisosteus oculatus ( a basal ray-finned fish), and the elephant shark Callorhinchus milii ( a cartilaginous fish). The CRH2 gene has been lost independently in placental mammals and in teleost fish, but is present in birds ( except chicken), anole lizard, and the nonplacental mammals platypus and opossum. Teleost 3R resulted in an additional surviving duplicate only for crh1 in some teleosts including zebrafish ( crh1a and crh1b). We have previously reported that the two vertebrate CRH/UCN receptors arose in 2R and that CRHR1 was duplicated in 3R. Thus, we can now conclude that this peptide-receptor system was quite complex in the ancestor of the jawed vertebrates with five CRH/UCN peptides and two receptors, and that crh and crhr1 were duplicated in the teleost fish tetraploidization.
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| 3. |
- Cen, Jing, et al.
(författare)
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Mechanisms of beneficial effects of metformin on fatty acid-treated human islets
- 2018
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041 .- 1479-6813. ; 61:3, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- Elevated levels of palmitate accentuate glucose-stimulated insulin secretion (GSIS) after short-term and cause beta-cell dysfunction after prolonged exposure. We investigated whether metformin, the first-line oral drug for treatment of T2DM, has beneficial effects on FFA-treated human islets and the potential mechanisms behind the effects. Insulin secretion, oxygen consumption rate (OCR), AMPK activation, endoplasmic reticulum (ER) stress and apoptosis were examined in isolated human islets after exposure to elevated levels of palmitate in the absence or presence of metformin. Palmitate exposure doubled GSIS after 2 days but halved after 7 days compared with control. Inclusion of metformin during palmitate exposure normalized insulin secretion both after 2 and 7 days. After 2-day exposure to palmitate, OCR and the marker of the adaptive arm of ER stress response (sorcin) were significantly raised, whereas AMPK phosphorylation, markers of pro-apoptotic arm of ER stress response (p-EIF2α and CHOP) and apoptosis (cleaved caspase 3) were not affected. Presence of metformin during 2-day palmitate exposure normalized OCR and sorcin levels. After 7-day exposure to palmitate, OCR and sorcin were not significantly different from control level, p-AMPK was reduced and p-EIF2α, CHOP and cleaved caspase 3 were strongly upregulated. Presence of metformin during 7-day culture with palmitate normalized the level of p-AMPK, p-EIF2α, CHOP and cleaved caspase 3 but significantly increased the level of sorcin. Our study demonstrates that metformin prevents early insulin hypersecretion and later decrease in insulin secretion from palmitate-treated human islets by utilizing different mechanisms.
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| 4. |
- Farman, Helen H., 1983, et al.
(författare)
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Extra-nuclear effects of estrogen on cortical bone in males require ERαAF-1
- 2017
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 58:2, s. 105-111
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Tidskriftsartikel (refereegranskat)abstract
- Estradiol (E2) signaling via estrogen receptor alpha (ERα) is important for the male skeleton as demonstrated by ERα inactivation in both mice and man. ERα mediates estrogenic effects not only by translocating to the nucleus and affecting gene transcription but also by extra-nuclear actions e.g., triggering cytoplasmic signaling cascades. ERα contains various domains, and the role of activation function 1 (ERαAF-1) is known to be tissue specific. The aim of this study was to determine the importance of extra-nuclear estrogen effects for the skeleton in males and to determine the role of ERαAF-1 for mediating these effects. Five-month-old male wild-type (WT) and ERαAF-1-inactivated (ERαAF-10) mice were orchidectomized and treated with equimolar doses of 17β-estradiol (E2) or an estrogen dendrimer conjugate (EDC), which is incapable of entering the nucleus and thereby only initiates extra-nuclear ER actions or their corresponding vehicles for 3.5 weeks. As expected, E2 treatment increased cortical thickness and trabecular bone volume per total volume (BV/TV) in WT males. EDC treatment increased cortical thickness in WT males, whereas no effect was detected in trabecular bone. In ERαAF-10 males, E2 treatment increased cortical thickness, but did not affect trabecular bone. Interestingly, the effect of EDC on cortical bone was abolished in ERαAF-10 mice. In conclusion, extra-nuclear estrogen signaling affects cortical bone mass in males, and this effect is dependent on a functional ERαAF-1. Increased knowledge regarding estrogen signaling mechanisms in the regulation of the male skeleton may aid the development of new treatment options for male osteoporosis.
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| 5. |
- Gong, Ningping, 1979, et al.
(författare)
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Acute anorexigenic action of leptin in rainbow trout is mediated by the hypothalamic Pi3k pathway
- 2016
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 56:3, s. 227-238
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Tidskriftsartikel (refereegranskat)abstract
- Leptin (Lep) is an anorexigenic hormone and regulates appetite-related neuropeptides in mammals. A number of neuropeptides have also been linked to appetite regulation in teleost fish, but Lep signaling activation and effects on appetite-regulating neurons are poorly elucidated in early vertebrates. This study uses cellular, tissue and organismal approaches to elucidate the acute, central Lep action in rainbow trout. The results demonstrate that Lep activates phosphorylation of protein kinase B (Akt) and signal transducer and activator of transcription 3 in rainbow trout hypothalamus-derived cells, and that the phosphatidylinositol-3-kinase (Pi3k) inhibitor LY294002 can suppress the Lep-induced Akt phosphorylation. Intracerebroventricular (ICV) Lep administration strongly suppresses food intake at the doses of 0.05 and 0.5 μg Lep fish-1. At low dose, Lep stimulates hypothalamic transcription of anorexigenic cocaine- and amphetamineregulated transcript (Cart) and orexigenic neuropeptide Y. At high dose, Lep stimulates hypothalamic transcription of anorexigenic proopiomelanocortin (Pomc) A1, A2, and B, while coinjection with LY294002 reverses this upregulation. The data suggest that the anorexigenic action of Lep in rainbow trout is mediated through stimulation of the anorexigenic neuropeptides Pomc and Cart. Furthermore, ICV Lep treatment increases phosphor-Akt-immunoreactive cells in the nucleus lateralis tuberis, periventricular zone along infundibulum, and lateral recess surrounded by nucleus anterior tuberis, while LY294002 inhibits this effect. Lep receptor-immunoreactive cells are also predominant in these regions. These results demonstrate that Lep activates the Pi3k-Akt pathway in the lateral tuberal hypothalamus of rainbow trout for acute appetite regulation, indicating the conservation of anorexigenic Lep action in the mediobasal hypothalamus. © 2016 Society for Endocrinology.
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| 6. |
- Hansson, Björn, et al.
(författare)
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Intact glucose uptake despite deteriorating signaling in adipocytes with high-fat feeding
- 2018
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 60:3, s. 199-211
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Tidskriftsartikel (refereegranskat)abstract
- To capture immediate cellular changes during diet-induced expansion of adipocyte cell volume and number, we characterized mature adipocytes during a short-term high-fat diet (HFD) intervention. Male C57BL6/J mice were fed chow diet, and then switched to HFD for 2, 4, 6 or 14 days. Systemic glucose clearance was assessed by glucose tolerance test. Adipose tissue was dissected for RNA-seq and cell size distribution analysis using coulter counting. Insulin response in isolated adipocytes was monitored by glucose uptake assay and Western blotting, and confocal microscopy was used to assess autophagic activity. Switching to HFD was accompanied by an immediate adipocyte size expansion and onset of systemic insulin resistance already after two days, followed by recruitment of new adipocytes. Despite an initially increased non-stimulated and preserved insulin-stimulated glucose uptake, we observed a decreased phosphorylation of insulin receptor substrate-1 (IRS-1) and protein kinase B (PKB). After 14 days of HFD, both the insulin-stimulated phosphorylation of Akt substrate of 160 kDa (AS160) and glucose uptake was blunted. RNA-seq analysis of adipose tissue revealed transient changes in gene expression at day four, including highly significant upregulation of Trp53inp, previously demonstrated to be involved in autophagy. We confirmed increased autophagy, measured as an increased density of LC3-positive puncta and decreased p62 expression after 14 days of HFD. In conclusion, HFD rapidly induced systemic insulin resistance, whereas insulin-stimulated glucose uptake remained intact throughout 6 days of HFD feeding. We also identified autophagy as an early cellular process that potentially influences adipocyte function upon switching to HFD.
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| 7. |
- Tubbs, Emily, et al.
(författare)
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Metabolic signaling functions of ER–mitochondria contact sites : Role in metabolic diseases
- 2017
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041. ; 58:2, s. 87-106
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Forskningsöversikt (refereegranskat)abstract
- Beyond the maintenance of cellular homeostasis and the determination of cell fate, ER– mitochondria contact sites, defined as mitochondria-associated membranes (MAM), start to emerge as an important signaling hub that integrates nutrient and hormonal stimuli and adapts cellular metabolism. Here, we summarize the established structural and functional features of MAM and mainly focus on the latest breakthroughs highlighting a crucial role of organelle crosstalk in the control of metabolic homeostasis. Lastly, we discuss recent studies that have revealed the importance of MAM in not only metabolic diseases but also in other pathologies with disrupted metabolism, shedding light on potential common molecular mechanisms and leading hopefully to novel treatment strategies.
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| 8. |
- Welsh, Michael, et al.
(författare)
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The role of the Src Homology-2 domain containing protein B (SHB) in β cells
- 2015
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Ingår i: Journal of Molecular Endocrinology. - 0952-5041 .- 1479-6813. ; 56:1, s. R21-R31
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Forskningsöversikt (refereegranskat)abstract
- This review will describe the SH2-domain signaling protein Src Homology-2 domaincontaining protein B (SHB) and its role in various physiological processes relating inparticular to glucose homeostasis andbcell function. SHB operates downstream of severaltyrosine kinase receptors and assembles signaling complexes in response to receptoractivation by interacting with other signaling proteins via its other domains (proline-rich,phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responsesare context-dependent. Absence ofShbin mice has been found to exert effects onhematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulinsecretion in response to glucose was impaired and this effect was related to alteredcharacteristics of focal adhesion kinase activation modulating signaling through Akt, ERK,bcatenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses tovarious stimuli by simultaneously modulating cellular responses in different cell-types, thusplaying a role in maintaining physiological homeostasis
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