The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
Abstract Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/gluc...
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2024-11-01
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| author | M. Pilar Valdecantos Laura Ruiz Cintia Folgueira Patricia Rada Beatriz Gomez-Santos Maite Solas Ana B. Hitos Joss Field Vera Francisco Carmen Escalona-Garrido Sebastián Zagmutt María Calderon-Dominguez Paula Mera Irma Garcia-Martinez Elsa Maymó-Masip Diana Grajales Rosa Alen Alfonso Mora Neira Sáinz Irene Vides-Urrestarazu Nuria Vilarrasa José M. Arbones-Mainar Carlos Zaragoza María J. Moreno-Aliaga Patricia Aspichueta Sonia Fernández-Veledo Joan Vendrell Dolors Serra Laura Herrero Renate Schreiber Rudolf Zechner Guadalupe Sabio David Hornigold Cristina M. Rondinone Lutz Jermutus Joseph Grimsby Ángela M. Valverde |
| author_facet | M. Pilar Valdecantos Laura Ruiz Cintia Folgueira Patricia Rada Beatriz Gomez-Santos Maite Solas Ana B. Hitos Joss Field Vera Francisco Carmen Escalona-Garrido Sebastián Zagmutt María Calderon-Dominguez Paula Mera Irma Garcia-Martinez Elsa Maymó-Masip Diana Grajales Rosa Alen Alfonso Mora Neira Sáinz Irene Vides-Urrestarazu Nuria Vilarrasa José M. Arbones-Mainar Carlos Zaragoza María J. Moreno-Aliaga Patricia Aspichueta Sonia Fernández-Veledo Joan Vendrell Dolors Serra Laura Herrero Renate Schreiber Rudolf Zechner Guadalupe Sabio David Hornigold Cristina M. Rondinone Lutz Jermutus Joseph Grimsby Ángela M. Valverde |
| author_sort | M. Pilar Valdecantos |
| collection | DOAJ |
| description | Abstract Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways. |
| format | Article |
| id | doaj-art-6e46df4151b04affa21678e1243d004d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-6e46df4151b04affa21678e1243d004d2024-12-01T12:33:26ZengNature PortfolioNature Communications2041-17232024-11-0115112910.1038/s41467-024-54080-wThe dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalkM. Pilar Valdecantos0Laura Ruiz1Cintia Folgueira2Patricia Rada3Beatriz Gomez-Santos4Maite Solas5Ana B. Hitos6Joss Field7Vera Francisco8Carmen Escalona-Garrido9Sebastián Zagmutt10María Calderon-Dominguez11Paula Mera12Irma Garcia-Martinez13Elsa Maymó-Masip14Diana Grajales15Rosa Alen16Alfonso Mora17Neira Sáinz18Irene Vides-Urrestarazu19Nuria Vilarrasa20José M. Arbones-Mainar21Carlos Zaragoza22María J. Moreno-Aliaga23Patricia Aspichueta24Sonia Fernández-Veledo25Joan Vendrell26Dolors Serra27Laura Herrero28Renate Schreiber29Rudolf Zechner30Guadalupe Sabio31David Hornigold32Cristina M. Rondinone33Lutz Jermutus34Joseph Grimsby35Ángela M. Valverde36Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridCentro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos IIIInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridDepartment of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHUDepartment of Pharmaceutical Sciences, Division of Pharmacology, University of NavarraInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridDepartment of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de BarcelonaDepartment of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de BarcelonaDepartment of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de BarcelonaInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos IIIInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridCentro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos IIIUniversity of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and PhysiologyUniversity of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and PhysiologyCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERcv), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos IIIDepartment of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHUCentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos IIICentro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos IIIInstitute of Molecular Biosciences, University of GrazInstitute of Molecular Biosciences, University of GrazCentro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos IIIBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca LtdBioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZenecaResearch and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca LtdInstituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de MadridAbstract Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.https://doi.org/10.1038/s41467-024-54080-w |
| spellingShingle | M. Pilar Valdecantos Laura Ruiz Cintia Folgueira Patricia Rada Beatriz Gomez-Santos Maite Solas Ana B. Hitos Joss Field Vera Francisco Carmen Escalona-Garrido Sebastián Zagmutt María Calderon-Dominguez Paula Mera Irma Garcia-Martinez Elsa Maymó-Masip Diana Grajales Rosa Alen Alfonso Mora Neira Sáinz Irene Vides-Urrestarazu Nuria Vilarrasa José M. Arbones-Mainar Carlos Zaragoza María J. Moreno-Aliaga Patricia Aspichueta Sonia Fernández-Veledo Joan Vendrell Dolors Serra Laura Herrero Renate Schreiber Rudolf Zechner Guadalupe Sabio David Hornigold Cristina M. Rondinone Lutz Jermutus Joseph Grimsby Ángela M. Valverde The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk Nature Communications |
| title | The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk |
| title_full | The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk |
| title_fullStr | The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk |
| title_full_unstemmed | The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk |
| title_short | The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk |
| title_sort | dual glp 1 glucagon receptor agonist g49 mimics bariatric surgery effects by inducing metabolic rewiring and inter organ crosstalk |
| url | https://doi.org/10.1038/s41467-024-54080-w |
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