Article abstract
Nature Chemical Biology 5, 749 - 757 (2009)
Published online: 13 July 2009 | doi:10.1038/nchembio.209
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents
Jonathan W Day1, Nickki Ottaway1, James T Patterson1, Vasily Gelfanov1, David Smiley1, Jas Gidda3, Hannes Findeisen4, Dennis Bruemmer4, Daniel J Drucker5, Nilika Chaudhary2, Jenna Holland2, Jazzminn Hembree2, William Abplanalp2, Erin Grant2, Jennifer Ruehl2, Hilary Wilson2, Henriette Kirchner2, Sarah Haas Lockie2, Susanna Hofmann6, Stephen C Woods2, Ruben Nogueiras2, Paul T Pfluger2, Diego Perez-Tilve2, Richard DiMarchi1 & Matthias H Tschöp2,6
Abstract
We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
- Obesity Research Centre, Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA.
- Marcadia Biotech, Carmel, Indiana, USA.
- Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
- Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio, USA.
Correspondence to: Richard DiMarchi1 e-mail: rdimarch@indiana.edu
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