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

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.

• Authors: 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 Sebokova, Karin Conde-Knape, Anish Konkar, Daniel J Drucker, Vasily Gelfanov, Paul T Pfluger, Timo D Müller, Diego Perez-Tilve, Richard D DiMarchi, Matthias H Tschöp
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 1 Pg. 27-36 (Jan 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 25485909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Peptides
• Receptors, Gastrointestinal Hormone
• Receptors, Glucagon
• Glucagon-Like Peptide 1
• gastric inhibitory polypeptide receptor

Topics

• Animals
• Blood Glucose (drug effects)
• Body Weight (genetics)
• Diabetes Complications (drug therapy, genetics, metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, genetics, metabolism)
• Glucagon-Like Peptide 1 (agonists, metabolism)
• HEK293 Cells
• Humans
• Insulin (biosynthesis, metabolism)
• Mice
• Obesity (drug therapy, genetics, metabolism)
• Peptides (administration & dosage, chemical synthesis, metabolism)
• Rats
• Receptors, Gastrointestinal Hormone (agonists, metabolism)
• Receptors, Glucagon (agonists, metabolism)
• Rodentia