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.

G49, a dual glucagon/glucagon-like peptide-1 receptor agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas and liver, leading to brown fat activation with the final outcomes of increased energy expenditure and body weight loss.

Details

Title
The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
Author
Valdecantos, M. Pilar 1   VIAFID ORCID Logo  ; Ruiz, Laura 2 ; Folgueira, Cintia 3   VIAFID ORCID Logo  ; Rada, Patricia 2   VIAFID ORCID Logo  ; Gomez-Santos, Beatriz 4   VIAFID ORCID Logo  ; Solas, Maite 5   VIAFID ORCID Logo  ; Hitos, Ana B. 2 ; Field, Joss 6   VIAFID ORCID Logo  ; Francisco, Vera 7 ; Escalona-Garrido, Carmen 2 ; Zagmutt, Sebastián 8 ; Calderon-Dominguez, María 8 ; Mera, Paula 8 ; Garcia-Martinez, Irma 2 ; Maymó-Masip, Elsa 9 ; Grajales, Diana 2 ; Alen, Rosa 2 ; Mora, Alfonso 10   VIAFID ORCID Logo  ; Sáinz, Neira 11 ; Vides-Urrestarazu, Irene 11 ; Vilarrasa, Nuria 12 ; Arbones-Mainar, José M. 13 ; Zaragoza, Carlos 14   VIAFID ORCID Logo  ; Moreno-Aliaga, María J. 15 ; Aspichueta, Patricia 16   VIAFID ORCID Logo  ; Fernández-Veledo, Sonia 17   VIAFID ORCID Logo  ; Vendrell, Joan 17   VIAFID ORCID Logo  ; Serra, Dolors 18   VIAFID ORCID Logo  ; Herrero, Laura 18   VIAFID ORCID Logo  ; Schreiber, Renate 19   VIAFID ORCID Logo  ; Zechner, Rudolf 19 ; Sabio, Guadalupe 10 ; Hornigold, David 6   VIAFID ORCID Logo  ; Rondinone, Cristina M. 20 ; Jermutus, Lutz 6   VIAFID ORCID Logo  ; Grimsby, Joseph 21 ; Valverde, Ángela M. 2   VIAFID ORCID Logo 

1  Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Faculty of Experimental Science, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (GRID:grid.449795.2) (ISNI:0000 0001 2193 453X) 
2  Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427) 
3  Instituto de Salud Carlos III, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain (GRID:grid.7719.8) (ISNI:0000 0000 8700 1153); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427) 
4  University of the Basque Country UPV/EHU, Department of Physiology, Faculty of Medicine and Nursing, Leioa, Spain (GRID:grid.11480.3c) (ISNI:0000 0001 2167 1098); BioBizkaia Health Research Institute, Barakaldo, Spain (GRID:grid.11480.3c) 
5  University of Navarra, Department of Pharmaceutical Sciences, Division of Pharmacology, Pamplona, Spain (GRID:grid.5924.a) (ISNI:0000 0004 1937 0271); Navarra Institute for Health Research, IdISNA, Pamplona, Spain (GRID:grid.508840.1) (ISNI:0000 0004 7662 6114) 
6  AstraZeneca, Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, Cambridge, UK (GRID:grid.417815.e) (ISNI:0000 0004 5929 4381) 
7  Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Madrid, Spain (GRID:grid.466793.9) (ISNI:0000 0004 1803 1972) 
8  Universitat de Barcelona, Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
9  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut d’Investigació Sanitària Pere Virgili (IISPV), Department of Endocrinology and Nutrition, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain (GRID:grid.420268.a) (ISNI:0000 0004 4904 3503) 
10  Instituto de Salud Carlos III, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain (GRID:grid.7719.8) (ISNI:0000 0000 8700 1153) 
11  Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain (GRID:grid.5924.a) (ISNI:0000 0004 1937 0271) 
12  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); L’Hospitalet de Llobregat, Obesity Unit and Endocrinology and Nutrition Departments, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain (GRID:grid.411129.e) (ISNI:0000 0000 8836 0780) 
13  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Hospital Universitario Miguel Servet, Adipocyte and Fat Biology Laboratory (AdipoFat), Unidad de Investigación Traslacional, Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain (GRID:grid.411106.3) (ISNI:0000 0000 9854 2756) 
14  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERcv), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Unidad de Investigación Cardiovascular, Universidad Francisco de Vitoria/Servicio de Cardiología, Madrid, Spain (GRID:grid.420232.5) (ISNI:0000 0004 7643 3507) 
15  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Navarra Institute for Health Research, IdISNA, Pamplona, Spain (GRID:grid.508840.1) (ISNI:0000 0004 7662 6114); Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain (GRID:grid.5924.a) (ISNI:0000 0004 1937 0271) 
16  University of the Basque Country UPV/EHU, Department of Physiology, Faculty of Medicine and Nursing, Leioa, Spain (GRID:grid.11480.3c) (ISNI:0000 0001 2167 1098); BioBizkaia Health Research Institute, Barakaldo, Spain (GRID:grid.11480.3c); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain (GRID:grid.452371.6) (ISNI:0000 0004 5930 4607) 
17  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut d’Investigació Sanitària Pere Virgili (IISPV), Department of Endocrinology and Nutrition, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain (GRID:grid.420268.a) (ISNI:0000 0004 4904 3503); Rovira I Virgili University (URV), Tarragona, Spain (GRID:grid.410367.7) (ISNI:0000 0001 2284 9230) 
18  Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universitat de Barcelona, Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
19  Institute of Molecular Biosciences, University of Graz, Graz, Austria (GRID:grid.5110.5) (ISNI:0000 0001 2153 9003) 
20  AstraZeneca Ltd, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, Gaithersburg, USA (GRID:grid.418152.b) (ISNI:0000 0004 0543 9493); Pep2Tango Therapeutics Inc., Potomac, USA (GRID:grid.418152.b) 
21  AstraZeneca Ltd, Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, Gaithersburg, USA (GRID:grid.418152.b) (ISNI:0000 0004 0543 9493); Internal Medicine, Regeneron Pharmaceuticals, Inc., Tarrytown, USA (GRID:grid.418961.3) (ISNI:0000 0004 0472 2713) 
Pages
10342
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-54080-w
ProQuest document ID
3133866629
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.