GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Endothelial sensing of AHR ligands regulates intestinal homeostasis
    Springer Science and Business Media LLC ; 2023
    In:  Nature Vol. 621, No. 7980 ( 2023-09-28), p. 821-829
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 621, No. 7980 ( 2023-09-28), p. 821-829
    Abstract: Endothelial cells line the blood and lymphatic vasculature, and act as an essential physical barrier, control nutrient transport, facilitate tissue immunosurveillance and coordinate angiogenesis and lymphangiogenesis 1,2 . In the intestine, dietary and microbial cues are particularly important in the regulation of organ homeostasis. However, whether enteric endothelial cells actively sense and integrate such signals is currently unknown. Here we show that the aryl hydrocarbon receptor (AHR) acts as a critical node for endothelial cell sensing of dietary metabolites in adult mice and human primary endothelial cells. We first established a comprehensive single-cell endothelial atlas of the mouse small intestine, uncovering the cellular complexity and functional heterogeneity of blood and lymphatic endothelial cells. Analyses of AHR-mediated responses at single-cell resolution identified tissue-protective transcriptional signatures and regulatory networks promoting cellular quiescence and vascular normalcy at steady state. Endothelial AHR deficiency in adult mice resulted in dysregulated inflammatory responses and the initiation of proliferative pathways. Furthermore, endothelial sensing of dietary AHR ligands was required for optimal protection against enteric infection. In human endothelial cells, AHR signalling promoted quiescence and restrained activation by inflammatory mediators. Together, our data provide a comprehensive dissection of the effect of environmental sensing across the spectrum of enteric endothelia, demonstrating that endothelial AHR signalling integrates dietary cues to maintain tissue homeostasis by promoting endothelial cell quiescence and vascular normalcy.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-023-06508-4
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Image_4.tiff
    Frontiers Media SA ; 2021
    In:  Frontiers in Endocrinology Vol. 12 ( 2021-12-17)
    Details
    In: Frontiers in Endocrinology, Frontiers Media SA, Vol. 12 ( 2021-12-17)
    Abstract: We evaluated the efficacy of a novel brain permeable “metformin-like” AMP-activated protein kinase activator, R481, in regulating glucose homeostasis. Materials and Methods We used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively. Results In vitro , we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro , R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo . Conclusions These data demonstrate that peripheral administration of the brain permeable “metformin-like” AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.
    Type of Medium: Online Resource
    ISSN: 1664-2392
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fendo.2021.697445
    DOI: 10.3389/fendo.2021.697445.s001
    DOI: 10.3389/fendo.2021.697445.s002
    DOI: 10.3389/fendo.2021.697445.s003
    DOI: 10.3389/fendo.2021.697445.s004
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2592084-4
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    AMP ‐activated protein kinase ( AMPK ) activator A ‐769662 increases intracellular calcium and ATP release from astrocytes in an AMPK ‐independent manner
    Wiley ; 2017
    In:  Diabetes, Obesity and Metabolism Vol. 19, No. 7 ( 2017-07), p. 997-1005
    Details
    In: Diabetes, Obesity and Metabolism, Wiley, Vol. 19, No. 7 ( 2017-07), p. 997-1005
    Abstract: To test the hypothesis that, given the role of AMP ‐activated protein kinase ( AMPK ) in regulating intracellular ATP levels, AMPK may alter ATP release from astrocytes, the main sources of extracellular ATP ( eATP ) within the brain. Materials and Methods Measurements of ATP release were made from human U373 astrocytoma cells, primary mouse hypothalamic ( HTAS ) and cortical astrocytes ( CRTAS ) and wild‐type and AMPK α1/α2 null mouse embryonic fibroblasts ( MEFs ). Cells were treated with drugs known to modulate AMPK activity: A ‐769662, AICAR and metformin, for up to 3 hours. Intracellular calcium was measured using F luo4 and F ura‐2 calcium‐sensitive fluorescent dyes. Results In U373 cells, A ‐769662 (100 μM) increased AMPK phosphorylation, whereas AICAR and metformin (1 mM) induced a modest increase or had no effect, respectively. Only A ‐769662 increased eATP levels, and this was partially blocked by AMPK inhibitor C ompound C . A‐769662‐induced increases in eATP were preserved in AMPK α1/α2 null MEF cells. A‐769662 increased intracellular calcium in U373 , HTAS and CRTAS cells and chelation of intracellular calcium using BAPTA‐AM reduced A ‐769662‐induced eATP levels. A‐769662 also increased ATP release from a number of other central and peripheral endocrine cell types. Conclusions AMPK is required to maintain basal eATP levels but is not required for A ‐769662‐induced increases in eATP . A‐769662 ( 〉 50 μM) enhanced intracellular calcium levels leading to ATP release in an AMPK and purinergic receptor independent pathway.
    Type of Medium: Online Resource
    ISSN: 1462-8902 , 1463-1326
    URL: Issue
    URL: Article
    DOI: 10.1111/dom.2017.19.issue-7
    DOI: 10.1111/dom.12912
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2004918-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Basal fatty acid oxidation increases after recurrent low glucose in human primary astrocytes
    Springer Science and Business Media LLC ; 2019
    In:  Diabetologia Vol. 62, No. 1 ( 2019-1), p. 187-198
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 62, No. 1 ( 2019-1), p. 187-198
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/s00125-018-4744-6
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 1458993-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Oleate induces K ATP channel-dependent hyperpolarization in mouse hypothalamic glucose-excited neurons without altering cellular energy charge
    Elsevier BV ; 2017
    In:  Neuroscience Vol. 346 ( 2017-03), p. 29-42
    Details
    In: Neuroscience, Elsevier BV, Vol. 346 ( 2017-03), p. 29-42
    Type of Medium: Online Resource
    ISSN: 0306-4522
    URL: Article
    DOI: 10.1016/j.neuroscience.2016.12.053
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 1498423-4
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Substrate recognition by the cell surface palmitoyl transferase DHHC5
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 49 ( 2014-12-09), p. 17534-17539
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 49 ( 2014-12-09), p. 17534-17539
    Abstract: The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme–substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1413627111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    119-OR: Amplified Glucagon Response to Hypoglycemia following AMP-Activated Protein Kinase (AMPK) Activator R481 Treatment in Healthy Rats
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Episodes of insulin-induced hypoglycemia are frequent in type 1 and advanced type 2 diabetes, but pharmaceutical approaches to prevent these are lacking. Cellular stresses such as low blood sugar activate AMPK, which has emerged as a whole body and cellular energy sensor. Direct delivery of AMPK activator to the ventromedial hypothalamus of rodents leads to increased hepatic glucose-production, observed during hyperinsulinemic-hypoglycemic clamp studies, and genetic activation of AMPK in the pancreatic alpha cell increases glucagon release. It may therefore be suitable to target AMPK for hypoglycemia prevention. Here, R481, a novel metformin-like brain permeable AMPK activator, was used to assess the impact of AMPK pathway activation on the counterregulatory response to hypoglycemia. Hypothalamic glucose sensing GT1-7 cells were treated with R481 and activation of AMPK pathway by phosphorylation assessed using Western Blotting. R481 was administered orally to male Sprague Dawley rats prior to insulin-induced hypoglycemia, following which blood glucose and feeding were measured. A separate cohort of rats underwent a hyperinsulinemic-hypoglycemic clamp study where glucose infusion rates and counterregulatory hormones levels were determined. Nanomolar concentrations of R481 increased AMPK pathway phosphorylation in GT1-7 neurons. Administration of R481 (5-20 mg/kg) to rats attenuated insulin-mediated drop in blood glucose during acute insulin-induced hypoglycemia, without altering fast-induced refeeding. R481 decreased the glucose infusion rate during hyperinsulinemic-hypoglycemic clamps, by amplifying plasma glucagon secretion, without altering epinephrine. Peripheral administration of AMPK activator R481 amplified glucagon release to improve counterregulatory response to hypoglycemia in healthy rats. Disclosure A.M.L. Cruz: None. Y. Malekizadeh: None. J.M. Vlachaki Walker: None. S.J. Shaw: Employee; Self; Rigel Pharmaceuticals. K.L. Ellacott: None. C. Beall: None. Funding JDRF; Diabetes UK
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-119-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...