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Nature communications
11 28, 2024;15 (1): 10342.

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
Author Information
  1. M Pilar Valdecantos: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. pvaldecantos@iib.uam.es. ORCID
  2. Laura Ruiz: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  3. Cintia Folgueira: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  4. Patricia Rada: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. ORCID
  5. Beatriz Gomez-Santos: Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain. ORCID
  6. Maite Solas: Department of Pharmaceutical Sciences, Division of Pharmacology, University of Navarra, Pamplona, Spain. ORCID
  7. Ana B Hitos: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  8. Joss Field: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ORCID
  9. Vera Francisco: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  10. Carmen Escalona-Garrido: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  11. 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, Barcelona, Spain.
  12. 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, Barcelona, Spain.
  13. 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, Barcelona, Spain.
  14. Irma Garcia-Martinez: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  15. Elsa Maymó-Masip: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
  16. Diana Grajales: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  17. Rosa Alen: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
  18. Alfonso Mora: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  19. Neira Sáinz: University of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, 31008, Pamplona, Spain.
  20. Irene Vides-Urrestarazu: University of Navarra, Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, 31008, Pamplona, Spain.
  21. Nuria Vilarrasa: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain.
  22. José M Arbones-Mainar: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
  23. Carlos Zaragoza: Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERcv), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  24. María J Moreno-Aliaga: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
  25. Patricia Aspichueta: Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain. ORCID
  26. Sonia Fernández-Veledo: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  27. Joan Vendrell: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  28. Dolors Serra: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  29. Laura Herrero: Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain. ORCID
  30. Renate Schreiber: Institute of Molecular Biosciences, University of Graz, 8010, Graz, Austria. ORCID
  31. Rudolf Zechner: Institute of Molecular Biosciences, University of Graz, 8010, Graz, Austria.
  32. Guadalupe Sabio: Centro Nacional de Investigaciones Cardiovasculares (CNIC), Instituto de Salud Carlos III, Madrid, Spain.
  33. David Hornigold: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ORCID
  34. Cristina M Rondinone: Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca Ltd, Gaithersburg, MD, USA.
  35. Lutz Jermutus: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ORCID
  36. Joseph Grimsby: Research and Early Development, Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca Ltd, Gaithersburg, MD, USA.
  37. Ángela M Valverde: Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain. avalverde@iib.uam.es. ORCID
PMID: 39609390 DOI: 10.1038/s41467-024-54080-w

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.

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Grants

  1. PID-2021-122766OB-100/Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
  2. RTI2018-094052-B-100/Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
  3. PID-2021-122766OB-100/Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)
  4. P2022/BMD-7227/Comunidad de Madrid
  5. P2022/BMD-7227/Comunidad de Madrid

MeSH Term

Humans
Bariatric Surgery
Animals
Glucagon-Like Peptide-1 Receptor
Obesity
Male
Energy Metabolism
Liver
Oxyntomodulin
Adipose Tissue, White
Fibroblast Growth Factors
Mice
Adipose Tissue, Brown
Mice, Inbred C57BL
Adiponectin
Pancreas
Fatty Acids, Nonesterified
Weight Loss
Female
Glucagon-Like Peptide-1 Receptor Agonists

Chemicals

Glucagon-Like Peptide-1 Receptor
Oxyntomodulin
Fibroblast Growth Factors
fibroblast growth factor 21
Adiponectin
Fatty Acids, Nonesterified
Glucagon-Like Peptide-1 Receptor Agonists
Journal Article Research Support, Non-U.S. Gov't

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