GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice

Animals and housing conditions Experiments were performed in accordance with the Animal Protection Law of the European Union after permission by the Governments of Upper Bavaria, Germany, or Copenhagen, Denmark, or by the Institutional Animal Care and Use Committees of the Universities of Texas Southwestern, Michigan, Duke or Yale, USA. Mice were double- or single-housed and unless otherwise indicated fed ad libitum with either a regular chow (1314, Altromin or 5L0D, LabDiet) or HFD (58% fat, D12331, Research Diets) under constant ambient conditions of 22 ± 2 °C with constant humidity (45–65%) and a 12 h:12 h light:dark cycle. Leptin receptor-deficient db/db mice were purchased from the Jacksons Laboratory (Strain 000697). Doxycyclin-inducible GIPR-overexpressing mice (TRE-GIPR mice) were generated in-house at The University of Texas Southwestern Medical Center as described previously 41 . C57BL/6J DIR-knockout mice were generated in-house at Helmholtz Munich (Supplementary Information 1 ). Pharmacological studies Indirect calorimetry and assessment of body composition was performed as described in Supplementary information 1 . Drug effects were assessed in age-matched male single-, or double-housed C57BL6/J mice that were randomly assigned in groups matched for genotype, body weight and body composition (fat and lean tissue mass). …