A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Brian Finan, Bin Yang, Nickki Ottaway, David L. Smiley, Tao Ma, Christoffer Clemmensen, Joe Chabenne, Lianshan Zhang, Kirk M. Habegger, Katrin Fischer, Jonathan E. Campbell, Darleen Sandoval, Randy J. Seeley, Konrad Bleicher, Sabine Uhles, William Riboulet, Jürgen Funk, Cornelia Hertel, Sara Belli, Elena SebokovaKarin Conde-Knape, Anish Konkar, Daniel J. Drucker, Vasily Gelfanov, Paul T. Pfluger, Timo D. Müller, Diego Perez-Tilve, Richard D. DiMarchi, Matthias H. Tschöp

Research output: Contribution to journalArticlepeer-review

497 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)27-36
Number of pages10
JournalNature Medicine
Volume21
Issue number1
DOIs
StatePublished - 1 Jan 2015

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