GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice

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. Overall design: 35 week-old DIO mice were treated 2 h prior to the end of the light phase with a single s.c. injection of either vehicle (PBS), acyl-GIP (150 nmol/kg)11-13, acyl-GLP-1 (50 nmol/kg)11-13, the GIPR:GLP1R co-agonist MAR709 (50 nmol/kg)11-13, or an acylated peptide GIPR antagonist (1,500 nmol/kg)20. Hypothalamus and hindbrain were harvested 8 h after drug administration and stored in liquid nitrogen. Nuclei were isolated using the 10X Genomics Chromium Nuclei Isolation Kit including RNase Inhibitor (10X Genomics; Pleasanton, CA, USA; #PN-1000494), and using the 10X Genomics protocol for Single Cell Multiome ATAC + Gene Expression (10X Genomics; Pleasanton, CA, USA; #CG000505 Rev A). Only the GEX data are included in this submission.