Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion
Objective: In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287781730008X |
| _version_ | 1828760754574065664 |
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| author | Céline Cruciani-Guglielmacci Lara Bellini Jessica Denom Masaya Oshima Neïké Fernandez Priscilla Normandie-Levi Xavier P. Berney Nadim Kassis Claude Rouch Julien Dairou Tracy Gorman David M. Smith Anna Marley Robin Liechti Dmitry Kuznetsov Leonore Wigger Frédéric Burdet Anne-Laure Lefèvre Isabelle Wehrle Ingo Uphues Tobias Hildebrandt Werner Rust Catherine Bernard Alain Ktorza Guy A. Rutter Raphael Scharfmann Ioannis Xenarios Hervé Le Stunff Bernard Thorens Christophe Magnan Mark Ibberson |
| author_facet | Céline Cruciani-Guglielmacci Lara Bellini Jessica Denom Masaya Oshima Neïké Fernandez Priscilla Normandie-Levi Xavier P. Berney Nadim Kassis Claude Rouch Julien Dairou Tracy Gorman David M. Smith Anna Marley Robin Liechti Dmitry Kuznetsov Leonore Wigger Frédéric Burdet Anne-Laure Lefèvre Isabelle Wehrle Ingo Uphues Tobias Hildebrandt Werner Rust Catherine Bernard Alain Ktorza Guy A. Rutter Raphael Scharfmann Ioannis Xenarios Hervé Le Stunff Bernard Thorens Christophe Magnan Mark Ibberson |
| author_sort | Céline Cruciani-Guglielmacci |
| collection | DOAJ |
| description | Objective: In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress. Methods: Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis. Results: A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines. Conclusion: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress. Keywords: Diabetes, Pancreas, Beta cell dysfunction, Network analysis, Molecular phenotyping, Metabolic stress |
| first_indexed | 2024-12-11T01:17:40Z |
| format | Article |
| id | doaj.art-64a96d3c764e447db5466d3eb59128b0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-11T01:17:40Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-64a96d3c764e447db5466d3eb59128b02022-12-22T01:25:48ZengElsevierMolecular Metabolism2212-87782017-04-0164340351Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretionCéline Cruciani-Guglielmacci0Lara Bellini1Jessica Denom2Masaya Oshima3Neïké Fernandez4Priscilla Normandie-Levi5Xavier P. Berney6Nadim Kassis7Claude Rouch8Julien Dairou9Tracy Gorman10David M. Smith11Anna Marley12Robin Liechti13Dmitry Kuznetsov14Leonore Wigger15Frédéric Burdet16Anne-Laure Lefèvre17Isabelle Wehrle18Ingo Uphues19Tobias Hildebrandt20Werner Rust21Catherine Bernard22Alain Ktorza23Guy A. Rutter24Raphael Scharfmann25Ioannis Xenarios26Hervé Le Stunff27Bernard Thorens28Christophe Magnan29Mark Ibberson30Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceINSERM U1016, Université Paris-Descartes, Institut Cochin, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceCentre for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, FranceDiscovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UKDiscovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UKDiscovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UKVital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandVital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandVital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandVital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandRecherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, FranceRecherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, FranceBoehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, GermanyBoehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, GermanyBoehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, GermanyRecherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, FranceRecherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, FranceSection of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London W120NN, UKINSERM U1016, Université Paris-Descartes, Institut Cochin, Paris, FranceVital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, SwitzerlandUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France; I2BC – UMR 9198 Université Paris Sud, Gif sur Yvette, FranceCentre for Integrative Genomics, University of Lausanne, 1015 Lausanne, SwitzerlandUnité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France; Corresponding author.Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Corresponding author. Vital-IT Group, SIB Swiss Institute of Bioinformatics, Genopode Building, University of Lausanne, Quartier Sorge, 1015 Lausanne, Switzerland.Objective: In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress. Methods: Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis. Results: A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines. Conclusion: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress. Keywords: Diabetes, Pancreas, Beta cell dysfunction, Network analysis, Molecular phenotyping, Metabolic stresshttp://www.sciencedirect.com/science/article/pii/S221287781730008X |
| spellingShingle | Céline Cruciani-Guglielmacci Lara Bellini Jessica Denom Masaya Oshima Neïké Fernandez Priscilla Normandie-Levi Xavier P. Berney Nadim Kassis Claude Rouch Julien Dairou Tracy Gorman David M. Smith Anna Marley Robin Liechti Dmitry Kuznetsov Leonore Wigger Frédéric Burdet Anne-Laure Lefèvre Isabelle Wehrle Ingo Uphues Tobias Hildebrandt Werner Rust Catherine Bernard Alain Ktorza Guy A. Rutter Raphael Scharfmann Ioannis Xenarios Hervé Le Stunff Bernard Thorens Christophe Magnan Mark Ibberson Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion Molecular Metabolism |
| title | Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion |
| title_full | Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion |
| title_fullStr | Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion |
| title_full_unstemmed | Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion |
| title_short | Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion |
| title_sort | molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for elovl2 in glucose induced insulin secretion |
| url | http://www.sciencedirect.com/science/article/pii/S221287781730008X |
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