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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Finan, B; Yang, B; Ottaway, N; Smiley, DL; Ma, T; Clemmensen, C; Chabenne, J; Zhang, L; Habegger, KM; Fischer, K; Campbell, JE; Sandoval, D; Seeley, RJ; Bleicher, K; Uhles, S; Riboulet, W; Funk, J; Hertel, C; Belli, S; Sebokova, E; Conde-Knape, K; Konkar, A; Drucker, DJ; Gelfanov, V; Pfluger, PT; Müller, TD; Perez-Tilve, D; DiMarchi, RD; Tschöp, MH

Published Date

  • January 2015

Published In

Volume / Issue

  • 21 / 1

Start / End Page

  • 27 - 36

PubMed ID

  • 25485909

Pubmed Central ID

  • 25485909

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm.3761

Language

  • eng