TY - JOUR
T1 - GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice
AU - Gutgesell, Robert M.
AU - Khalil, Ahmed
AU - Liskiewicz, Arkadiusz
AU - Maity-Kumar, Gandhari
AU - Novikoff, Aaron
AU - Grandl, Gerald
AU - Liskiewicz, Daniela
AU - Coupland, Callum
AU - Karaoglu, Ezgi
AU - Akindehin, Seun
AU - Castelino, Russell
AU - Curion, Fabiola
AU - Liu, Xue
AU - Garcia-Caceres, Cristina
AU - Cebrian-Serrano, Alberto
AU - Douros, Jonathan D.
AU - Knerr, Patrick J.
AU - Finan, Brian
AU - DiMarchi, Richard D.
AU - Sloop, Kyle W.
AU - Samms, Ricardo J.
AU - Theis, Fabian J.
AU - Tschöp, Matthias H.
AU - Müller, Timo D.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
AB - Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
UR - http://www.scopus.com/inward/record.url?scp=105003832243&partnerID=8YFLogxK
U2 - 10.1038/s42255-025-01294-x
DO - 10.1038/s42255-025-01294-x
M3 - Article
AN - SCOPUS:105003832243
SN - 2522-5812
JO - Nature Metabolism
JF - Nature Metabolism
M1 - 4981
ER -
