GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist–Induced Nausea and Emesis in Preclinical Models

TLDR

GLP‑1R agonists lower body weight and improve glycemic control, but their clinical use is limited by nausea and emesis mediated through hindbrain AP/NTS circuits. 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. In mice, rats, and musk shrews, GIPR activation blocks GLP‑1R‑induced emesis and illness behaviors while preserving weight loss and glucose control, and single‑nuclei RNA‑seq shows GIPR is expressed on distinct GABAergic neurons in the AP/NTS.

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.