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GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice
Robert M Gutgesell1,2,3, Ahmed Khalil1,2, Arkadiusz Liskiewicz1,2,4
1Institute for Diabetes and Obesity, Helmholtz, Munich, Germany.
Nature Metabolism
|April 29, 2025
Summary
Glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism reduces body weight and food intake, but requires functional glucagon-like peptide-1 receptor (GLP-1R) signaling. This differs from GIPR agonism
Area of Science:
- Metabolic regulation and neuroendocrinology.
- Pharmacology of peptide hormone receptors.
- Molecular mechanisms of appetite control.
Background:
- Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) are known to enhance weight loss from glucagon-like peptide-1 receptor (GLP-1R) agonism.
- GIPR agonism reduces body weight and food intake independently of GLP-1R signaling, acting through GABAergic GIPR+ neurons.
- The precise mechanism by which GIPR antagonism influences energy metabolism remains unclear.
Purpose of the Study:
- To investigate whether GIPR antagonism affects energy metabolism through a mechanism similar to GIPR agonism.
- To elucidate the differential roles of GIPR agonism and antagonism in regulating body weight and food intake.
- To determine the dependence of GIPR antagonism's metabolic effects on GLP-1R signaling and specific neuronal populations.
Main Methods:
- Utilized genetically modified mice with global or cell-specific deletions of Gipr and Glp-1r.
- Administered GIPR antagonists and assessed effects on body weight and food intake.
- Employed single-nucleus RNA-sequencing (snRNA-seq) in the dorsal vagal complex.
- Analyzed gene expression related to synaptic plasticity.
Main Results:
- The body weight and food intake effects of GIPR antagonism were abolished in mice lacking either Gipr or Glp-1r globally.
- These effects were preserved in mice with Gipr loss specifically in central GABAergic neurons or peripheral neurons.
- Single-nucleus RNA-sequencing revealed opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism mimicking GLP-1R signaling.
- Both GIPR antagonism and GLP-1R agonism modulated genes involved in synaptic plasticity.
Conclusions:
- GIPR agonism and antagonism decrease body weight through distinct mechanisms.
- GIPR antagonism's effects on body weight and food intake are dependent on functional GLP-1R signaling.
- Unlike GIPR agonism, GIPR antagonism's metabolic actions are not mediated by central GABAergic GIPR+ neurons but rely on GLP-1R pathways.
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