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

Article · Novikoff A, O'Brien SL, Bernecker M, Grandl G, Kleinert M, Knerr PJ, Stemmer K, Klingenspor M, Zeigerer A, DiMarchi R, Tschöp MH, Finan B, Calebiro D, Müller TD

- Archive id: doi:10.1016/j.molmet.2021.101181
- Published: 2021-02-06
- Venue: Molecular metabolism
- DOI: https://doi.org/10.1016/j.molmet.2021.101181
- PMID: 33556643
- PMCID: PMC7921015
- Citations: 87
- Source URL: https://doi.org/10.1016/j.molmet.2021.101181
- PDF: https://europepmc.org/articles/PMC7921015/pdf
- Provenance: europepmc

## Abstract

Objective We assessed 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 native and acylated GLP-1 agonists, MAR709 and tirzepatide showed 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 indicated that MAR709 and tirzepatide induce unique spatiotemporal GLP-1 and GIP receptor signaling, trafficking, and recycling dynamics relative to native peptides, semaglutide, and matched mono-agonist controls. These findings support the hypothesis that the structure of GLP-1/GIP dual-agonists confer a biased agonism that, in addition to its influence on intracellular signaling, uniquely modulates receptor trafficking.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [GLP-1 & Incretin Therapies](https://space-kitty.com/topics/glp1-metabolic)

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