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

Publication ,  Journal Article
Finan, B; Yang, B; Ottaway, N; Smiley, DL; Ma, T; Clemmensen, C; Chabenne, J; Zhang, L; Habegger, KM; Fischer, K; Campbell, JE; Sandoval, D ...
Published in: Nat Med
January 2015

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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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2015

Volume

21

Issue

1

Start / End Page

27 / 36

Location

United States

Related Subject Headings

  • Rodentia
  • Receptors, Glucagon
  • Receptors, Gastrointestinal Hormone
  • Rats
  • Peptides
  • Obesity
  • Mice
  • Insulin
  • Immunology
  • Humans
 

Citation

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Finan, B., Yang, B., Ottaway, N., Smiley, D. L., Ma, T., Clemmensen, C., … Tschöp, M. H. (2015). A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med, 21(1), 27–36. https://doi.org/10.1038/nm.3761
Finan, Brian, Bin Yang, Nickki Ottaway, David L. Smiley, Tao Ma, Christoffer Clemmensen, Joe Chabenne, et al. “A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.Nat Med 21, no. 1 (January 2015): 27–36. https://doi.org/10.1038/nm.3761.
Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015 Jan;21(1):27–36.
Finan, Brian, et al. “A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.Nat Med, vol. 21, no. 1, Jan. 2015, pp. 27–36. Pubmed, doi:10.1038/nm.3761.
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. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015 Jan;21(1):27–36.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

January 2015

Volume

21

Issue

1

Start / End Page

27 / 36

Location

United States

Related Subject Headings

  • Rodentia
  • Receptors, Glucagon
  • Receptors, Gastrointestinal Hormone
  • Rats
  • Peptides
  • Obesity
  • Mice
  • Insulin
  • Immunology
  • Humans