Liskiewicz, Arkadiusz; Khalil, Ahmed; Liskiewicz, Daniela; Novikoff, Aaron; Grandl, Gerald; Maity-Kumar, Gandhari; Gutgesell, Robert M; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Czarnecki, Oliver; Makris, Konstantinos; Lickert, Heiko; Feuchtinger, Annette; Tost, Monica; Coupland, Callum; Ständer, Lisa; Akindehin, Seun; Prakash, Sneha; Abrar, Faiyaz; Castelino, Russell L; He, Yantao; Knerr, Patrick J; Yang, Bin; Hogendorf, Wouter F J; Zhang, Shiqi; Hofmann, Susanna M; Finan, Brian; DiMarchi, Richard D; Tschöp, Matthias H; Douros, Jonathan D; Müller, Timo D     «

Liskiewicz, Arkadiusz; Khalil, Ahmed; Liskiewicz, Daniela; Novikoff, Aaron; Grandl, Gerald; Maity-Kumar, Gandhari; Gutgesell, Robert M; Bakhti, Mostafa; Bastidas-Ponce, Aimée; Czarnecki, Oliver; Makris, Konstantinos; Lickert, Heiko; Feuchtinger, Annette; Tost, Monica; Coupland, Callum; Ständer, Lisa; Akindehin, Seun; Prakash, Sneha; Abrar, Faiyaz; Castelino, Russell L; He, Yantao; Knerr, Patrick J; Yang, Bin; Hogendorf, Wouter F J; Zhang, Shiqi; Hofmann, Susanna M; Finan, Brian; DiMarchi, Richar...     »

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6-8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR-GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.      «

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence su...     »