The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk
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.
Authors
- María J. Moreno‐Aliaga (ORCID: https://orcid.org/0000-0002-2018-6434)
- M. Pilar Valdecantos
- Alfonso Mora (ORCID: https://orcid.org/0000-0002-6397-4836)
- Laura Herrero (ORCID: https://orcid.org/0000-0003-4244-4673)
- Angela Martinez Valverde (ORCID: https://orcid.org/0000-0003-1192-9045)
- José M. Arbones-Mainar (ORCID: https://orcid.org/0000-0002-8982-3737)
- Irma García‐Martinez (ORCID: https://orcid.org/0000-0002-8828-6888)
- Vera Francisco (ORCID: https://orcid.org/0000-0002-2404-6607)
- Paula Mera (ORCID: https://orcid.org/0000-0001-8941-4637)
- David C. Hornigold (ORCID: https://orcid.org/0000-0002-3354-2768)
- María Calderón‐Domínguez (ORCID: https://orcid.org/0000-0003-1797-3450)
- Cintia Folgueira (ORCID: https://orcid.org/0000-0003-3803-9149)
- Joan Josep Vendrell (ORCID: https://orcid.org/0000-0002-6994-6115)
- Diana Grajales (ORCID: https://orcid.org/0000-0002-9332-6979)
- Laura Ruíz-Cañas (ORCID: https://orcid.org/0000-0002-4373-2573)
- Carlos Zaragoza (ORCID: https://orcid.org/0000-0002-1706-8592)
- Núria Vilarrasa (ORCID: https://orcid.org/0000-0003-3188-1990)
- Dolors Serra (ORCID: https://orcid.org/0000-0002-4936-4206)
- Renate Schreiber (ORCID: https://orcid.org/0000-0002-3475-157X)
- Ana B. Hitos
- Cristina M. Rondinone
- Lutz Jermutus (ORCID: https://orcid.org/0000-0001-7660-8467)
- Rudolf Zechner (ORCID: https://orcid.org/0000-0001-5483-1182)
- Carmen Escalona-Garrido
- Sonia Fernández‐Veledo (ORCID: https://orcid.org/0000-0003-2906-3788)
- Beatriz Gómez‐Santos (ORCID: https://orcid.org/0000-0001-6607-7973)
- Guadalupe Sabio (ORCID: https://orcid.org/0000-0002-2822-0625)
- Patricia Rada (ORCID: https://orcid.org/0000-0002-6731-2098)
- Neira Sáinź (ORCID: https://orcid.org/0000-0003-0298-3031)
- Rosa Alén (ORCID: https://orcid.org/0000-0003-1876-2612)
- Sebastián Zagmutt (ORCID: https://orcid.org/0000-0001-6050-4452)
- Patricia Aspichueta (ORCID: https://orcid.org/0000-0002-3553-1755)
- Joseph Grimsby (ORCID: https://orcid.org/0000-0002-0388-1427)
- Maite Solas (ORCID: https://orcid.org/0000-0001-7670-3237)
- Elsa Maymó‐Masip (ORCID: https://orcid.org/0000-0002-9133-3120)
- Irene Vides-Urrestarazu
- Joss Field (ORCID: https://orcid.org/0009-0009-9387-026X)
Institutions
- AstraZeneca (United Kingdom) (GB)
- Consejo Superior de Investigaciones Científicas (ES)
- University of Graz (AT)
- University of the Basque Country (ES)
- Regeneron (United States) (US)
- Universidad Francisco de Vitoria (ES)
- Instituto de Salud Carlos III (ES)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- BioCruces Health research Institute (ES)
- Spanish National Cancer Research Centre (ES)
- Instituto de Investigaciones Biomédicas Sols-Morreale (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Centro Nacional de Epidemiología (ES)
- Navarre Institute of Health Research (ES)
- Hospital Universitario Miguel Servet (ES)
- Centro de Investigación Biomédica en Red (ES)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- AstraZeneca (United States) (US)
- Io Therapeutics (United States) (US)
- Instituto Aragonés de Ciencias de la Salud (ES)
- Institut de Biomedicina de la Universitat de Barcelona
- Universitat Rovira i Virgili (ES)
- Universidad Autónoma de Madrid (ES)
- Universitat de Barcelona (ES)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1038/s41467-024-54080-w
- Citations
- 13
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Comunidad de Madrid
- Agencia Estatal de Investigación