Nature Communications (Nov 2024)
The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
- 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
Affiliations
- M. Pilar Valdecantos
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Laura Ruiz
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Cintia Folgueira
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III
- Patricia Rada
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Beatriz Gomez-Santos
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU
- Maite Solas
- Department of Pharmaceutical Sciences, Division of Pharmacology, University of Navarra
- Ana B. Hitos
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Joss Field
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
- Vera Francisco
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Carmen Escalona-Garrido
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Sebastián Zagmutt
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
- María Calderon-Dominguez
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
- Paula Mera
- Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona
- Irma Garcia-Martinez
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Elsa Maymó-Masip
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III
- Diana Grajales
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Rosa Alen
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- Alfonso Mora
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III
- Neira Sáinz
- University of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and Physiology
- Irene Vides-Urrestarazu
- University of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and Physiology
- Nuria Vilarrasa
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III
- José M. Arbones-Mainar
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III
- Carlos Zaragoza
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERcv), Instituto de Salud Carlos III
- María J. Moreno-Aliaga
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III
- Patricia Aspichueta
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU
- Sonia Fernández-Veledo
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III
- Joan Vendrell
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III
- Dolors Serra
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III
- Laura Herrero
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III
- Renate Schreiber
- Institute of Molecular Biosciences, University of Graz
- Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz
- Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III
- David Hornigold
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
- Cristina M. Rondinone
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca Ltd
- Lutz Jermutus
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca
- Joseph Grimsby
- Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca Ltd
- Ángela M. Valverde
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
- DOI
- https://doi.org/10.1038/s41467-024-54080-w
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 29
Abstract
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.
