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  1. Article ; Online: SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes.

    Sabadell-Basallote, Joan / Astiarraga, Brenno / Castaño, Carlos / Ejarque, Miriam / Repollés-de-Dalmau, Maria / Quesada, Ivan / Blanco, Jordi / Nuñez-Roa, Catalina / Rodríguez-Peña, M-Mar / Martínez, Laia / De Jesus, Dario F / Marroqui, Laura / Bosch, Ramon / Montanya, Eduard / Sureda, Francesc X / Tura, Andrea / Mari, Andrea / Kulkarni, Rohit N / Vendrell, Joan /
    Fernández-Veledo, Sonia

    The Journal of clinical investigation

    2024  

    Abstract: Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice ... ...

    Abstract Pancreatic β-cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here we report that the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Mice with β-cell-specific Sucnr1 deficiency exhibit impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance show an enhanced nutritional-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
    Language English
    Publishing date 2024-05-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI173214
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Glycogen accumulation in adipocyte precursors from elderly and obese subjects triggers inflammation via SIRT1/6 signaling.

    Terrón-Puig, Margarida / Huber-Ruano, Isabel / Sabadell-Basallote, Joan / Ejarque, Miriam / Núñez-Roa, Catalina / Maymó-Masip, Elsa / Jorba, Rosa / Serena, Carolina / Vendrell, Joan / Fernández-Veledo, Sonia

    Aging cell

    2022  Volume 21, Issue 8, Page(s) e13667

    Abstract: Dysfunctional adipocyte precursors have emerged as key determinants for obesity- and aging-related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals ... ...

    Abstract Dysfunctional adipocyte precursors have emerged as key determinants for obesity- and aging-related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals focusing on the metabolic and inflammatory state of human adipose-derived mesenchymal stromal cells (hASCs), and on sirtuins, which link metabolism and inflammation. Both obesity and aging impaired the differentiation potential of hASCs but had a different impact on their proliferative capacity. hASCs from elderly individuals (≥65 years) showed an upregulation of glycolysis-related genes, which was accompanied by increased lactate secretion and glycogen storage, a phenotype that was exaggerated by obesity. Multiplex protein profiling revealed that the metabolic switch to glycogenesis was associated with a pro-inflammatory secretome concomitant with a decrease in the protein expression of SIRT1 and SIRT6. siRNA-mediated knockdown of SIRT1 and SIRT6 in hASCs from lean adults increased the expression of pro-inflammatory and glycolysis-related markers, and enforced glycogen deposition by overexpression of protein targeting to glycogen (PTG) led to a downregulation of SIRT1/6 protein levels, mimicking the inflammatory state of hASCs from elderly subjects. Overall, our data point to a glycogen-SIRT1/6 signaling axis as a driver of age-related inflammation in adipocyte precursors.
    MeSH term(s) Adipocytes/metabolism ; Adipose Tissue/metabolism ; Adult ; Aged ; Glycogen/metabolism ; Humans ; Inflammation/metabolism ; Obesity/metabolism ; Sirtuin 1/genetics ; Sirtuin 1/metabolism ; Sirtuins/genetics ; Sirtuins/metabolism
    Chemical Substances Glycogen (9005-79-2) ; SIRT1 protein, human (EC 3.5.1.-) ; SIRT6 protein, human (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
    Language English
    Publishing date 2022-07-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/acel.13667
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Diabetes alters the protein secretome of human adipose-derived stem cells and promotes tumorigenesis in hepatic cancer cells.

    Ejarque, Miriam / Sabadell-Basallote, Joan / Benaiges, Ester / Núñez-Roa, Catalina / Sabido, Eduardo / Borras, Eva / Llacer, Erik / Zorzano, Antonio / Vendrell, Joan / Fernández-Veledo, Sonia

    Clinical and translational medicine

    2022  Volume 12, Issue 6, Page(s) e823

    MeSH term(s) Cell Transformation, Neoplastic/metabolism ; Diabetes Mellitus ; Humans ; Liver Neoplasms/metabolism ; Secretome ; Stem Cells/metabolism
    Language English
    Publishing date 2022-06-02
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697013-2
    ISSN 2001-1326 ; 2001-1326
    ISSN (online) 2001-1326
    ISSN 2001-1326
    DOI 10.1002/ctm2.823
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  4. Article ; Online: Effects of stem cells from inducible brown adipose tissue on diet-induced obesity in mice.

    Calvo, Enrique / Keiran, Noelia / Núñez-Roa, Catalina / Maymó-Masip, Elsa / Ejarque, Miriam / Sabadell-Basallote, Joan / Del Mar Rodríguez-Peña, María / Ceperuelo-Mallafré, Victòria / Seco, Jesús / Benaiges, Ester / Michalopoulou, Theodora / Jorba, Rosa / Vendrell, Joan / Fernández-Veledo, Sonia

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 13923

    Abstract: Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the ... ...

    Abstract Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.
    MeSH term(s) Adipose Tissue, White/pathology ; Adrenal Gland Neoplasms/pathology ; Animals ; Biomarkers/metabolism ; Diet ; Female ; Gene Expression Regulation ; Glucose/metabolism ; Humans ; Inflammation/genetics ; Lipid Metabolism/genetics ; Male ; Mice, Inbred C57BL ; Middle Aged ; Obesity/pathology ; Pheochromocytoma/pathology ; Stem Cells/pathology ; Weight Gain ; Mice
    Chemical Substances Biomarkers ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-07-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-93224-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: EndoC-βH5 cells are storable and ready-to-use human pancreatic beta cells with physiological insulin secretion.

    Blanchi, Bruno / Taurand, Marion / Colace, Claire / Thomaidou, Sofia / Audeoud, Charlotte / Fantuzzi, Federica / Sawatani, Toshiaki / Gheibi, Sevda / Sabadell-Basallote, Joan / Boot, Fransje W J / Chantier, Thibault / Piet, Aline / Cavanihac, Charlotte / Pilette, Marion / Balguerie, Adélie / Olleik, Hamza / Carlotti, Françoise / Ejarque, Miriam / Fex, Malin /
    Mulder, Hindrik / Cnop, Miriam / Eizirik, Decio L / Jouannot, Ouardane / Gaffuri, Anne-Lise / Czernichow, Paul / Zaldumbide, Arnaud / Scharfmann, Raphaël / Ravassard, Philippe

    Molecular metabolism

    2023  Volume 76, Page(s) 101772

    Abstract: Objectives: Readily accessible human pancreatic beta cells that are functionally close to primary adult beta cells are a crucial model to better understand human beta cell physiology and develop new treatments for diabetes. We here report the ... ...

    Abstract Objectives: Readily accessible human pancreatic beta cells that are functionally close to primary adult beta cells are a crucial model to better understand human beta cell physiology and develop new treatments for diabetes. We here report the characterization of EndoC-βH5 cells, the latest in the EndoC-βH cell family.
    Methods: EndoC-βH5 cells were generated by integrative gene transfer of immortalizing transgenes hTERT and SV40 large T along with Herpes Simplex Virus-1 thymidine kinase into human fetal pancreas. Immortalizing transgenes were removed after amplification using CRE activation and remaining non-excized cells eliminated using ganciclovir. Resulting cells were distributed as ready to use EndoC-βH5 cells. We performed transcriptome, immunological and extensive functional assays.
    Results: Ready to use EndoC-βH5 cells display highly efficient glucose dependent insulin secretion. A robust 10-fold insulin secretion index was observed and reproduced in four independent laboratories across Europe. EndoC-βH5 cells secrete insulin in a dynamic manner in response to glucose and secretion is further potentiated by GIP and GLP-1 analogs. RNA-seq confirmed abundant expression of beta cell transcription factors and functional markers, including incretin receptors. Cytokines induce a gene expression signature of inflammatory pathways and antigen processing and presentation. Finally, modified HLA-A2 expressing EndoC-βH5 cells elicit specific A2-alloreactive CD8 T cell activation.
    Conclusions: EndoC-βH5 cells represent a unique storable and ready to use human pancreatic beta cell model with highly robust and reproducible features. Such cells are thus relevant for the study of beta cell function, screening and validation of new drugs, and development of disease models.
    MeSH term(s) Humans ; Insulin-Secreting Cells/metabolism ; Insulin Secretion ; Cell Line ; Insulin/metabolism ; Transcription Factors/metabolism ; Glucose/metabolism
    Chemical Substances Insulin ; Transcription Factors ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2023-07-11
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2023.101772
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression.

    Villanueva-Carmona, Teresa / Cedó, Lídia / Madeira, Ana / Ceperuelo-Mallafré, Victòria / Rodríguez-Peña, M-Mar / Núñez-Roa, Catalina / Maymó-Masip, Elsa / Repollés-de-Dalmau, Maria / Badia, Joan / Keiran, Noelia / Mirasierra, Mercedes / Pimenta-Lopes, Carolina / Sabadell-Basallote, Joan / Bosch, Ramón / Caubet, Laura / Escolà-Gil, Joan Carles / Fernández-Real, José-Manuel / Vilarrasa, Nuria / Ventura, Francesc /
    Vallejo, Mario / Vendrell, Joan / Fernández-Veledo, Sonia

    Cell metabolism

    2023  Volume 35, Issue 4, Page(s) 601–619.e10

    Abstract: Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its ... ...

    Abstract Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.
    MeSH term(s) Animals ; Humans ; Mice ; Adipocytes/metabolism ; Circadian Clocks ; Energy Metabolism/physiology ; Leptin/metabolism ; Mice, Knockout ; Obesity/metabolism ; Succinates/metabolism
    Chemical Substances Leptin ; Succinates ; GPR91 protein, mouse
    Language English
    Publishing date 2023-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2023.03.004
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6169: Show issues Location:
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  7. Article ; Online: Adipose tissue is a key organ for the beneficial effects of GLP-2 metabolic function.

    Ejarque, Miriam / Sabadell-Basallote, Joan / Beiroa, Daniel / Calvo, Enrique / Keiran, Noelia / Nuñez-Roa, Catalina / Rodríguez, Maria Del Mar / Sabench, Fatima / Del Castillo, Daniel / Jimenez, Veronica / Bosch, Fatima / Nogueiras, Ruben / Vendrell, Joan / Fernández-Veledo, Sonia

    British journal of pharmacology

    2020  Volume 178, Issue 10, Page(s) 2131–2145

    Abstract: Background and purpose: Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to nutritional intake that exerts a wide range of effects by activating GLP-2 receptors. In addition to its intestinotrophic effects, GLP-2 also ... ...

    Abstract Background and purpose: Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone released in response to nutritional intake that exerts a wide range of effects by activating GLP-2 receptors. In addition to its intestinotrophic effects, GLP-2 also positively influences glucose metabolism under conditions of obesity, but the mechanisms behind this remain unclear. Here, we have investigated the molecular role of the GLP-2/GLP-2 receptor axis in energetic metabolism, focusing on its potential modulatory effects on adipose tissue.
    Experimental approach: Physiological measurements (body weight, food intake, locomotor activity, and energy expenditure) and metabolic studies (glucose and insulin tolerance tests) were performed on lean and obese mice treated with the protease-resistant GLP-2 analogue teduglutide.
    Key results: Acute but not chronic centrally administered teduglutide decreased food intake and weight-gain. By contrast, chronic activation of peripheral GLP-2 receptors increased body weight-independent glucose tolerance and had anti-inflammatory effects on visceral adipose tissue. Using a gene silencing approach, we found that adipose tissue is necessary for these beneficial effects of teduglutide. Finally, teduglutide regulates the inflammatory state and acts as an anabolic signal in human adipocytes.
    Conclusion and implications: Overall, our data identify adipose tissue as a new, clinically relevant, site of action for GLP-2 activity in obesity.
    Linked articles: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
    MeSH term(s) Adipose Tissue ; Body Weight ; Eating ; Glucagon-Like Peptide 2 ; Humans ; Obesity/drug therapy
    Chemical Substances Glucagon-Like Peptide 2
    Language English
    Publishing date 2020-11-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.15278
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