Publication: The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk.
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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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This work was funded by grants RTI2018-094052-B-100 funded by MICIU/AEI/10.13039/501100011033/ and by ERDF “A way of making Europe” and PID-2021-122766OB-100 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU, P2022/BMD-7227 (Comunidad de Madrid, Spain) and CIBERDdem (ISCIII) to A.M.V. and M.P.V., grants PID2020-114953RB-C21
funded by MICIU/AEI/10.13039/501100011033 to L.H. and D.S., CB06/03/0001 (CIBERobn, ISCIII, Spain) and 2021SGR00367 (Government of Catalonia) to L.H., grants PID2019-106982RB-I00 funded by MICIU/AEI/10.13039/501100011033 and CB12/03/30002 (CIBERobn, ISCIII, Spain) to M.J.M.-A., grants AECC PROYE19047SABI, PMP21/00057 Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología IMPACT2021, Instituto de Salud Carlos III, PDC2021-121147-I00 funded by MICIU/
AEI/10.13039/501100011033 and the “European Union NextGeneration/PRTR” and PID2022-138525OB-I00 funded by MICIU/AEI/10.13039/501100011033 and ERDF/EU to G.S., grant PID2021-122480OB-100 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU, and 2021 SGR 01409 (Generalitat de Catalunya) to S.F.V., grant PID2021-128737NB-I00 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU to M.S., grants PI20/00338, PI23/01133 (ISCIII, Spain), and 2021 SGR 00829 (Government of Catalunya) to J.V., grants PI17/01556 and PI22/01773 (ISCIII, Spain) to N.V., grants IT1476-22 funded by Basque Government, Department of Education and PID2021-124425OB-100 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU to P.A. and F7302 SFB‐Lipid‐Hydrolysis from the Austrian Science Fund FWF and 12CVD04 from the Leducq Foundation both to R.Z. C.F. was funded by EASO/Novo Nordisk New Investigator Award in Basic Sciences 2023, EFSD/Novo Nordisk Rising Star 2024 and IBSA Foundation Fellowship
Endocrinology 2023. V.F. was supported by “Albert Renold Travel Fellowship” grant from EFSD. Magnetic resonance imaging studies were performed at BioImaC (BioImagen Complutense), a node of the ICTS ReDIB. We acknowledge F. Gribble and F. Reimann (Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK) for the GLP-1R mAb, E.
Fernández Valle and David Moreno Molera (BioImaC, UCM, Madrid) for assisting in the body composition analysis and Angela Montes-San Lorenzo for technical assistance. We also acknowledge all members of A.M.V.’s laboratory for helpful discussions.
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Nat Commun. 2024 Nov 28;15(1):10342.