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Novikoff, A. ; O'Brien, S.L.* ; Bernecker, M. ; Grandl, G. ; Kleinert, M. ; Knerr, P.J.* ; Stemmer, K. ; Klingenspor, M.* ; Zeigerer, A. ; DiMarchi, R.* ; Tschöp, M.H. ; Finan, B.* ; Calebiro, D.* ; Müller, T.D.

Spatiotemporal GLP-1 and GIPR receptor signaling and trafficking/recycling dynamics induced by selected receptor mono- and dual-agonists.

Mol. Metab. 49:101181 (2021)

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OBJECTIVE: We aimed to assess the spatiotemporal GLP-1 and GIP receptor signaling, trafficking and recycling dynamics of GIPR mono-agonists, GLP-1R mono-agonists including semaglutide, and GLP-1/GIP dual-agonists MAR709 and tirzepatide. METHODS: Receptor G protein recruitment and internalization/trafficking dynamics were assessed using bioluminescence resonance energy transfer (BRET)-based technology and live cell HILO microscopy. RESULTS: Relative to the native and acylated GLP-1 agonists, MAR709 and tirzepatide show preserved maximal cAMP production despite partial Gα_s recruitment paralleled by diminished ligand-induced receptor internalization at both target receptors. Despite MAR709's lower internalization rate, GLP-1R co-localization with Rab11-associated recycling endosomes was not different between MAR709 and GLP-1R specific mono-agonists. CONCLUSIONS: Our data indicate that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking and recycling dynamics relative to the native peptides, semaglutide and matched mono-agonist controls. These findings support the hypothesis that the structure of the GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Diabetes ; Gipr ; Glp-1r ; Obesity ; Biased Agonism ; Internalization

ISSN (print) / ISBN 2212-8778

e-ISSN 2212-8778

Journal Molecular Metabolism

Quellenangaben Volume: 49, Article Number: 101181

Publisher Elsevier

Publishing Place Amsterdam

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Cancer (IDC)