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.
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Acknowledgements
We thank K. Brown for skilled technical assistance and R. Seeley (University of Cincinnati), D. D'Alessio (University of Cincinnati) and S. Vignati (Marcadia Biotech) for expert advice and helpful discussions. We are grateful to J. Levy for his assistance in peptide synthesis, purification and characterization; J. Karty (Indiana University) and A. Hansen (Indiana University) for their expertise and support in mass spectrometry data collection and analysis; and B. Yang (Marcadia Biotech) for providing Fmoc l-homocysteic acid.
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J.W.D. designed, synthesized and characterized all peptides and co-wrote the manuscript. N.O. co-planned and led all in vivo studies and co-wrote the manuscript. J.T.P., V.G., D.S. and J.G. gave advice on chemical design, interpreted biological data and co-wrote the manuscript. H.F. and D.B. performed adipocyte studies, interpreted results and co-wrote the manuscript. D.J.D. provided mouse models, interpreted data and co-wrote the manuscript. W.A. performed in vitro studies including western blotting. N.C., J. Holland, J. Hembree, E.G., J.R., H.W., H.K. and S.H.L. co-performed all in vivo pharmacology and metabolism studies as a team. S.H. performed cholesterol and lipoprotein analysis studies. S.C.W. gave advice on experimental design, interpreted data and co-wrote the manuscript. R.N., P.T.P. and D.P.-T. co-planned, co-performed and supervised all in vivo and ex vivo biology studies. R.D. and M.H.T. conceptualized, analyzed and interpreted all studies and wrote the manuscript.
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R.D., M.T. and J.G. have partial ownership in Marcadia Biotech. Marcadia Biotech has provided partial research support for this work.
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Day, J., Ottaway, N., Patterson, J. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 5, 749–757 (2009). https://doi.org/10.1038/nchembio.209
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DOI: https://doi.org/10.1038/nchembio.209
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