Biased incretin receptor signaling to improve metabolic efficacy

Incretin receptor mono- and dual agonists targeting the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) represent highly effective therapies for obesity and type 2 diabetes (T2D). The receptors signal via Gαs and Gαq, recruit β-arrestin, and undergo ligand-dependent internalization. However, therapeutic efficacy depends not only on receptor activation but also on biased agonism, that is the selective engagement of distinct signaling pathways. Accordingly, GLP-1R/GIPR dual agonists exhibit biased signaling at GLP-1R, characterized by reduced Gαs/Gαq activation, limited β-arrestin recruitment, along with sustained cAMP signaling.

This project aims to define how biased agonism at GLP-1R and GIPR controls receptor signaling and downstream effector engagement, and how these processes determine the metabolic outcomes. We use animal models of obesity together with pharmacological and genetic approaches to selectively modulate candidate pathways, to perform metabolic phenotyping and to analyze pancreatic islet function. Advanced bioluminescence resonance energy transfer (BRET)-based biosensors enable us to quantify canonical G protein and β-arrestin signalling, the spatiotemporal organization of receptor signalling complexes and their interactions with downstream effectors in the metabolically relevant tissues.

A second focus is to elucidate the role of biased GIPR signaling in adipose tissue function. We use depot-specific human adipose tissue organoids derived from healthy and T2D donors to investigate GIPR-dependent signaling, lipolysis, and adipose secretome remodeling under pathophysiological conditions. By integrating adipose organoids with pancreatic islets, we investigate how adipose-derived factors regulate insulin secretion and GPCR signaling in beta cells.

By combining receptor pharmacology, biosensor technologies, animal physiology, and human organoid models, we seek to establish a mechanistic framework for biased incretin receptor signaling and its role in inter-organ communication.