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The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

Author

Listed:
  • M. Pilar Valdecantos

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III
    Faculty of Experimental Science, Universidad Francisco de Vitoria, Pozuelo de Alarcon)

  • Laura Ruiz

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Cintia Folgueira

    (Instituto de Salud Carlos III
    Centro Nacional de Investigaciones Oncológicas (CNIO)
    Instituto de Salud Carlos III)

  • Patricia Rada

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Beatriz Gomez-Santos

    (University of the Basque Country UPV/EHU
    BioBizkaia Health Research Institute)

  • Maite Solas

    (University of Navarra
    Navarra Institute for Health Research)

  • Ana B. Hitos

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Joss Field

    (AstraZeneca)

  • Vera Francisco

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid)

  • Carmen Escalona-Garrido

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Sebastián Zagmutt

    (Universitat de Barcelona)

  • María Calderon-Dominguez

    (Universitat de Barcelona)

  • Paula Mera

    (Universitat de Barcelona)

  • Irma Garcia-Martinez

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Elsa Maymó-Masip

    (Instituto de Salud Carlos III
    Institut d’Investigació Sanitària Pere Virgili (IISPV))

  • Diana Grajales

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Rosa Alen

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

  • Alfonso Mora

    (Instituto de Salud Carlos III
    Centro Nacional de Investigaciones Oncológicas (CNIO))

  • Neira Sáinz

    (Center for Nutrition Research and Department of Nutrition, Food Science and Physiology)

  • Irene Vides-Urrestarazu

    (Center for Nutrition Research and Department of Nutrition, Food Science and Physiology)

  • Nuria Vilarrasa

    (Instituto de Salud Carlos III
    L’Hospitalet de Llobregat)

  • José M. Arbones-Mainar

    (Instituto de Salud Carlos III
    Hospital Universitario Miguel Servet)

  • Carlos Zaragoza

    (Instituto de Salud Carlos III
    Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS))

  • María J. Moreno-Aliaga

    (Instituto de Salud Carlos III
    Navarra Institute for Health Research
    Center for Nutrition Research and Department of Nutrition, Food Science and Physiology)

  • Patricia Aspichueta

    (University of the Basque Country UPV/EHU
    BioBizkaia Health Research Institute
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd))

  • Sonia Fernández-Veledo

    (Instituto de Salud Carlos III
    Institut d’Investigació Sanitària Pere Virgili (IISPV)
    Rovira I Virgili University (URV))

  • Joan Vendrell

    (Instituto de Salud Carlos III
    Institut d’Investigació Sanitària Pere Virgili (IISPV)
    Rovira I Virgili University (URV))

  • Dolors Serra

    (Instituto de Salud Carlos III
    Universitat de Barcelona)

  • Laura Herrero

    (Instituto de Salud Carlos III
    Universitat de Barcelona)

  • Renate Schreiber

    (Institute of Molecular Biosciences, University of Graz)

  • Rudolf Zechner

    (Institute of Molecular Biosciences, University of Graz)

  • Guadalupe Sabio

    (Instituto de Salud Carlos III
    Centro Nacional de Investigaciones Oncológicas (CNIO))

  • David Hornigold

    (AstraZeneca)

  • Cristina M. Rondinone

    (AstraZeneca Ltd
    Pep2Tango Therapeutics Inc.)

  • Lutz Jermutus

    (AstraZeneca)

  • Joseph Grimsby

    (AstraZeneca Ltd
    Internal Medicine)

  • Ángela M. Valverde

    (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
    Instituto de Salud Carlos III)

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.

Suggested Citation

  • 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 & M, 2024. "The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54080-w
    DOI: 10.1038/s41467-024-54080-w
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    as
    1. Susanne Keipert & Dominik Lutter & Bjoern O. Schroeder & Daniel Brandt & Marcus Ståhlman & Thomas Schwarzmayr & Elisabeth Graf & Helmut Fuchs & Martin Hrabe Angelis & Matthias H. Tschöp & Jan Rozman &, 2020. "Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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