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 and Ángela M. Valverde ()
Additional contact information
M. Pilar Valdecantos: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
Laura Ruiz: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
Cintia Folgueira: Instituto de Salud Carlos III
Patricia Rada: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
Beatriz Gomez-Santos: University of the Basque Country UPV/EHU
Maite Solas: University of Navarra
Ana B. Hitos: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
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
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
Elsa Maymó-Masip: Instituto de Salud Carlos III
Diana Grajales: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
Rosa Alen: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
Alfonso Mora: Instituto de Salud Carlos III
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
José M. Arbones-Mainar: Instituto de Salud Carlos III
Carlos Zaragoza: Instituto de Salud Carlos III
María J. Moreno-Aliaga: Instituto de Salud Carlos III
Patricia Aspichueta: University of the Basque Country UPV/EHU
Sonia Fernández-Veledo: Instituto de Salud Carlos III
Joan Vendrell: Instituto de Salud Carlos III
Dolors Serra: Instituto de Salud Carlos III
Laura Herrero: 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: Instituto de Salud Carlos III
David Hornigold: AstraZeneca
Cristina M. Rondinone: AstraZeneca Ltd
Lutz Jermutus: AstraZeneca
Joseph Grimsby: AstraZeneca Ltd
Ángela M. Valverde: Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-54080-w

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