Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A new glucagon and GLP-1 co-agonist eliminates obesity in rodents

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure of glucagon, GLP-1 and chimeric peptides.
Figure 2: Structure of glucagon-based peptides using circular dichroism and a ligand-receptor model.
Figure 3: One-month treatment of diet-induced obese mice with glucagon and GLP-1 chimerae Aib2 C24 40k and Aib2 C24 lactam 40k.
Figure 4: One-month treatment of diet-induced obese mice with glucagon and GLP-1 chimerae Aib2 C24 40k and Aib2 C24 lactam 40k.
Figure 5: One-month treatment of diet-induced obese mice with glucagon and GLP-1 chimerae Aib2 C24 40k and Aib2 C24 lactam 40k.
Figure 6: Lipolytic impact of glucagon and GLP-1 chimerae Aib2 C24 40k and Aib2 C24 lactam 40k.
Figure 7: Effect of glucagon and GLP-1 chimerae Aib2 C24 40k and Aib2 C24 lactam in GLP-1R knockout mice.

Similar content being viewed by others

References

  1. Ogden, C.L. et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 295, 1549–1555 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Neovius, M. & Narbro, K. Cost-effectiveness of pharmacological anti-obesity treatments: a systematic review. Int. J. Obes. 32, 1752–1763 (2008).

    Article  CAS  Google Scholar 

  3. Cvetkovic, R.S. & Plosker, G.L. Exenatide - a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). Drugs 67, 935–954 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Gutniak, M., Orskov, C., Holst, J.J., Ahren, B. & Efendic, S. Antidiabetogenic effect of glucagon-like peptide-1 (7–36)amide in normal subjects and patients with diabetes-mellitus. N. Engl. J. Med. 326, 1316–1322 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Roth, J.D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl. Acad. Sci. USA 105, 7257–7262 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Woods, S.C., Lutz, T.A., Geary, N. & Langhans, W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1219–1235 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Geary, N., Kissileff, H.R., Pisunyer, F.X. & Hinton, V. Individual, but not simultaneous, glucagon and cholecystokinin infusions inhibit feeding in men. Am. J. Physiol. 262, R975–R980 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Geary, N. Pancreatic glucagon signals postprandial satiety. Neurosci. Biobehav. Rev. 14, 323–338 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Geary, N. Glucagon and the control of meal size. in Satiation: From Gut To Brain (ed. Smith, G.P.) 164–197 (Oxford University Press, USA, 1998).

    Chapter  Google Scholar 

  10. Goodridge, A.G. & Ball, E.G. Studies on metabolism of adipose tissue. 18. In vitro effects of insulin epinephrine and glucagon on lipolysis and glycolysis in pigeon adipose tissue. Comp. Biochem. Physiol. 16, 367–381 (1965).

    Article  CAS  PubMed  Google Scholar 

  11. Heckemeyer, C.M., Barker, J., Duckworth, W.C. & Solomon, S.S. Studies of the biological effect and degradation of glucagon in the rat perifused isolated adipose cell. Endocrinology 113, 270–276 (1983).

    Article  CAS  PubMed  Google Scholar 

  12. Davidson, I.W.F., Salter, J.M. & Best, C.H. The effect of glucagon on the metabolic rate of rats. Am. J. Clin. Nutr. 8, 540–546 (1960).

    Article  CAS  Google Scholar 

  13. Salter, J.M. Metabolic effects of glucagon in the Wistar rat. Am. J. Clin. Nutr. 8, 535–539 (1960).

    Article  CAS  Google Scholar 

  14. Chan, E.K. et al. Suppression of weight-gain by glucagon in obese Zucker rats. Exp. Mol. Pathol. 40, 320–327 (1984).

    Article  CAS  PubMed  Google Scholar 

  15. Hjorth, S.A., Adelhorst, K., Pedersen, B.B., Kirk, O. & Schwartz, T.W. Glucagon and glucagon-like peptide 1: selective receptor recognition via distinct peptide epitopes. J. Biol. Chem. 269, 30121–30124 (1994).

    CAS  PubMed  Google Scholar 

  16. Orskov, C. Glucagon-like peptide-1, a new hormone of the enteroinsular axis. Diabetologia 35, 701–711 (1992).

    CAS  PubMed  Google Scholar 

  17. Wynne, K. et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects - a double-blind, randomized, controlled trial. Diabetes 54, 2390–2395 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Baggio, L.L., Huang, Q.L., Brown, T.J. & Drucker, D.J. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 127, 546–558 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Small, C.J. & Bloom, S.R. Gut hormones and the control of appetite. Trends Endocrinol. Metab. 15, 259–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Cohen, M.A. et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J. Clin. Endocrinol. Metab. 88, 4696–4701 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Billington, C.J., Bartness, T.J., Briggs, J., Levine, A.S. & Morley, J.E. Glucagon stimulation of brown adipose-tissue growth and thermogenesis. Am. J. Physiol. 252, R160–R165 (1987).

    CAS  PubMed  Google Scholar 

  22. Runge, S. et al. Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus. J. Biol. Chem. 278, 28005–28010 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Runge, S., Wulff, B.S., Madsen, K., Brauner-Osborne, H. & Knudsen, L.B. Different domains of the glucagon and glucagon-like peptide-1 receptors provide the critical determinants of ligand selectivity. Br. J. Pharmacol. 138, 787–794 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Neidigh, J.W., Fesinmeyer, R.M., Prickett, K.S. & Andersen, N.H. Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states. Biochemistry 40, 13188–13200 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Runge, S., Thogersen, H., Madsen, K., Lau, J. & Rudolph, R. Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. J. Biol. Chem. 283, 11340–11347 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Scrocchi, L.A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Rucker, D., Padwal, R., Li, S.K., Curioni, C. & Lau, D.C.W. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335, 1194–1199 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Christensen, R., Kristensen, P.K., Bartels, E.M., Blidda, H. & Astrup, A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370, 1706–1713 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Griffen, L. & Anchors, M. Asymptomatic mitral and aortic valve disease is seen in half of the patients taking 'Phen-Fen'. Arch. Intern. Med. 158, 102 (1998).

  30. Amori, R.E., Lau, J. & Pittas, A.G. Efficacy and safety of incretin therapy in type 2 diabetes - systematic review and meta-analysis. JAMA 298, 194–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Savitzky, A. & Golay, M.J.E. Smoothing and differentiation of data by simplified least squares procedures. Anal. Chem. 36, 1627–1639 (1964).

    Article  CAS  Google Scholar 

  32. Whitmore, L. & Wallace, B.A. Protein secondary structure analyses from circular dichroism spectroscopy: methods and reference databases. Biopolymers 89, 392–400 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Whitmore, L. & Wallace, B.A. DICHROWEB, an online server for protein secondary structure analyses from circular dichroism spectroscopic data. Nucleic Acids Res. 32, W668–W673 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tinsley, F.C., Taicher, G.Z. & Heiman, M.L. Evaluation of a quantitative magnetic resonance method for mouse whole body composition analysis. Obes. Res. 12, 150–160 (2004).

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Richard DiMarchi.

Ethics declarations

Competing interests

R.D., M.T. and J.G. have partial ownership in Marcadia Biotech. Marcadia Biotech has provided partial research support for this work.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 6938 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.209

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing