GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models
Tito Borner, Caroline E. Geisler, Samantha M. Fortin, Richard Cosgrove, Jorge Alsina‐Fernandez, Mridula Dogra, Sarah A. Doebley, Marcos J. Sanchez-Navarro, Rosa M. Leon, Jane Gaisinsky, Arianna White, Ankur Bamezai, Misgana Y. Ghidewon, Harvey J. Grill, Richard C. Crist, Benjamin C. Reiner, Minrong Ai, Ricardo J. Samms, Bart C. De Jonghe, Matthew R. Hayes
Abstract
Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.