We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
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We thank J. Levy for technical and chemical support of peptide synthesis. We thank J. Ford for cell culture maintenance. We thank J. Patterson, J. Day, B. Ward and C. Ouyang for discussions on chemical structure-activity relationships and seminal work in mixed agonist peptides. We thank J. Holland, J. Hembree, C. Raver, S. Amburgy, J. Pressler, J. Sorrell, D. Küchler and L. Sehrer for assistance during in vivo pharmacological studies. At F. Hoffmann–La Roche Ltd., we thank A. Roeckel, A. Vandjour and E. Hainaut for assistance during in vivo pharmacological studies; M. Brecheisen, C. Richardson, G. Branellec and V. Ott for necropsy and immunohistological procedures; C. Apfel, C. Wohlgesinger and V. Griesser for bioanalytics; and M. Kapps, C. Flament, P. Schrag, C. Rapp, M.S. Gruyer, V. Dall′Asen, F. Schuler and M. Otteneder for assistance in pharmacokinetic studies. We thank M. Charron (Albert Einstein College of Medicine) for providing Gcgr−/− mice and Y. Seino (Kansai Electric Power Hospital) for providing Gipr−/− mice. Partial research funding was provided by Marcadia Biotech, which has been acquired by F. Hoffmann–La Roche Ltd., and by grants from the Deutsche Forschungsgesellschaft (DFG; TS226/1-1), Deutsches Zentrum für Diabetesforschung (DZD), EurOCHIP (FP-7-HEALTH-2009-241592), Helmholtz Alliance ICEMED–Imaging and Curing Environmental Metabolic Diseases (through the Initiative and Networking Fund of the Helmholtz Association) and the Canadian Institutes of Health Research (93749).
Supplementary Results, Supplementary Tables 1–6 and Supplementary Figures 1–8.