GIPR-Ab/GLP-1 Peptide-antibody Conjugate Requires CNS GIPRs and GLP-1Rs to Engage Anorexigenic Circuitry for Additive Weight Loss in Obese Mice

Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for additive effects on body weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR KO mice compared to WT mice, and the extent of weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. WT mice treated with GIPR-Ab/GLP-1 or CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodeling, lipid metabolism, and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signaling are required for the full effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate, with loss of CNS GIPR activity potentiating the actions of GLP-1R agonism. RNA-seq profiling of liver and inguinal white adipose tissue in Glpr1 fl/fl and GIPR fl/fl DIO mice with or without treatment of GIPR-Ab/P1; liver and inguinal white adipose in Glp1rWnt1-/- and GIPR syn-/- DIO mice treated with vehicle.