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Diabetes ; 70(11): 2545-2553, 2021 11.
Article in English | MEDLINE | ID: mdl-34380697

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.


Subject(s)
Glucagon-Like Peptide-1 Receptor/agonists , Nausea/chemically induced , Nausea/drug therapy , Receptors, Gastrointestinal Hormone/agonists , Animals , Body Weight/drug effects , Feeding Behavior , Male , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Shrews , Vomiting
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