Research Paper – GIPR Antagonism and GLP-1R Agonism Metabolic Effects

Gutgesell RM, Khalil A, Liskiewicz A, Maity-Kumar G, Novikoff A, Grandl G, Liskiewicz D, Coupland C, Karaoglu E, Akindehin S, Castelino R, Curion F, Liu X, Garcia-Caceres C, Cebrian-Serrano A, Douros JD, Knerr PJ, Finan B, DiMarchi RD, Sloop KW, Samms RJ, Theis FJ, Tschöp MH, Müller TD. GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice. Nat Metab. 2025 Apr 29. doi: 10.1038/s42255-025-01294-x. Epub ahead of print. PMID: 40301583.

This scientific paper explores the mechanisms by which GIPR agonism and antagonism influence body weight and food intake in mice, particularly in combination with GLP-1R agonism. While both GIPR approaches can promote weight loss, the research reveals they operate through distinct neural pathways. The study demonstrates that GIPR agonism acts via GABAergic neurons in a GLP-1R-independent manner, whereas GIPR antagonism requires functional GLP-1R signaling and does not depend on GIPR signaling in GABAergic or peripheral neurons. Single-nucleus RNA sequencing further supports this by showing opposing transcriptional effects of GIPR agonism and antagonism in the dorsal vagal complex, with GIPR antagonism closely resembling GLP-1R signaling. These findings suggest that targeting the GIPR can impact energy metabolism through different brain-based mechanisms.

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