Skip to main content

Thank you for visiting 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.

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



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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: In vivo demonstration of GLP-1, GIP and glucagon triple agonism through coadministration and unimolecular peptides.
Figure 2: Unimolecular triagonism maximizes metabolic benefits compared with dual incretin coagonism.
Figure 3: The metabolic and glycemic benefits of the triagonist are blunted in Glp1r−/−, Gipr−/− and Gcgr−/− mice.
Figure 4: Addition of glucagon activity contributes thermogenic character to the triagonist.
Figure 5: Balanced glucagon activity does not exacerbate hyperglycemia development.
Figure 6: Fine-tuning of glucagon activity within the triagonist alters metabolic and glycemic efficacies.


  1. 1

    Speakman, J.R. & O′Rahilly, S. Fat: an evolving issue. Dis. Model. Mech. 5, 569–573 (2012).

    CAS  Article  Google Scholar 

  2. 2

    Di Dalmazi, G., Vicennati, V., Pasquali, R. & Pagotto, U. The unrelenting fall of the pharmacological treatment of obesity. Endocrine 44, 598–609 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Rodgers, R.J., Tschop, M.H. & Wilding, J.P. Anti-obesity drugs: past, present and future. Dis. Model. Mech. 5, 621–626 (2012).

    CAS  Article  Google Scholar 

  4. 4

    Gadde, K.M. et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 377, 1341–1352 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Allison, D.B. et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring) 20, 330–342 (2012).

    CAS  Article  Google Scholar 

  6. 6

    Garvey, W.T. et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am. J. Clin. Nutr. 95, 297–308 (2012).

    CAS  Article  Google Scholar 

  7. 7

    Fosgerau, K. et al. The novel GLP-1-gastrin dual agonist, ZP3022, increases beta-cell mass and prevents diabetes in db/db mice. Diabetes Obes. Metab. 15, 62–71 (2013).

    CAS  Article  Google Scholar 

  8. 8

    Day, J.W. et al. A new glucagon and GLP-1 coagonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).

    CAS  Article  Google Scholar 

  9. 9

    Finan, B. et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 5, 209ra151 (2013).

    Article  Google Scholar 

  10. 10

    Pocai, A. et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Finan, B. et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Clemmensen, C. et al. GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes 63, 1422–1427 (2014).

    CAS  Article  Google Scholar 

  13. 13

    Sadry, S.A. & Drucker, D.J. Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat. Rev. Endocrinol. 9, 425–433 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Barrera, J.G., Sandoval, D.A., D'Alessio, D.A. & Seeley, R.J. GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7, 507–516 (2011).

    CAS  Article  Google Scholar 

  15. 15

    Campbell, J.E. & Drucker, D.J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013).

    CAS  Article  Google Scholar 

  16. 16

    Habegger, K.M. et al. The metabolic actions of glucagon revisited. Nat. Rev. Endocrinol. 6, 689–697 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Habegger, K.M. et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453–1463 (2013).

    CAS  Article  Google Scholar 

  18. 18

    Chabenne, J.R., DiMarchi, M.A., Gelfanov, V.M. & DiMarchi, R.D. Optimization of the native glucagon sequence for medicinal purposes. J. Diabetes Sci. Technol. 4, 1322–1331 (2010).

    Article  Google Scholar 

  19. 19

    Ward, B. et al. Peptide lipidation stabilizes structure to enhance biological function. Mol. Metab. 2, 468–479 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Yip, R.G., Boylan, M.O., Kieffer, T.J. & Wolfe, M.M. Functional GIP receptors are present on adipocytes. Endocrinology 139, 4004–4007 (1998).

    CAS  Article  Google Scholar 

  21. 21

    Panjwani, N. et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE−/−mice. Endocrinology 154, 127–139 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Patterson, J.T. et al. A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1. ACS Chem. Biol. 6, 135–145 (2011).

    CAS  Article  Google Scholar 

  23. 23

    European Medicines Agency. Assessment Report for Victoza; doc. ref. EMEA/379172/2009 (2009).

  24. 24

    Bhat, V.K., Kerr, B.D., Vasu, S., Flatt, P.R. & Gault, V.A.A. DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice. Diabetologia 56, 1417–1424 (2013).

    CAS  Article  Google Scholar 

  25. 25

    Gault, V.A., Bhat, V.K., Irwin, N. & Flatt, P.R. A novel GLP-1/glucagon hybrid peptide with triple-acting agonist activity at GIP, GLP-1 and glucagon receptors and therapeutic potential in high-fat-fed mice. J. Biol. Chem. 288, 35581–35591 (2013).

    CAS  Article  Google Scholar 

  26. 26

    Miyawaki, K. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738–742 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Gelling, R.W. et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc. Natl. Acad. Sci. USA 100, 1438–1443 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Day, J.W. et al. Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers 98, 443–450 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Scrocchi, L.A. & Drucker, D.J. Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor−/− mice. Endocrinology 139, 3127–3132 (1998).

    CAS  Article  Google Scholar 

  30. 30

    Kim, M. et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat. Med. 19, 567–575 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Mukharji, A., Drucker, D.J., Charron, M.J. & Swoap, S.J. Oxyntomodulin increases intrinsic heart rate through the glucagon receptor. Physiol. Rep. 1, e00112 (2013).

    Article  Google Scholar 

  32. 32

    Bhat, V.K., Kerr, B.D., Flatt, P.R. & Gault, V.A. A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties. Biochem. Pharmacol. 85, 1655–1662 (2013).

    CAS  Article  Google Scholar 

  33. 33

    Ionut, V., Burch, M., Youdim, A. & Bergman, R.N. Gastrointestinal hormones and bariatric surgery-induced weight loss. Obesity (Silver Spring) 21, 1093–1103 (2013).

    CAS  Article  Google Scholar 

  34. 34

    Muller, T.D. et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. J. Pept. Sci. 18, 383–393 (2012).

    Article  Google Scholar 

  35. 35

    Bénardeau, A. et al. Effects of the dual PPAR-α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat. Diabetes Obes. Metab. 15, 164–174 (2013).

    Article  Google Scholar 

  36. 36

    Uhles, S. et al. Taspoglutide, a novel human once-weekly GLP-1 analogue, protects pancreatic beta-cells in vitro and preserves islet structure and function in the Zucker diabetic fatty rat in vivo. Diabetes Obes. Metab. 13, 326–336 (2011).

    CAS  Article  Google Scholar 

Download references


We thank J. Levy for technical and chemical support of peptide synthesis. We thank J. Ford for cell culture maintenance. We thank J. Patterson, J. Day, B. Ward and C. Ouyang for discussions on chemical structure-activity relationships and seminal work in mixed agonist peptides. We thank J. Holland, J. Hembree, C. Raver, S. Amburgy, J. Pressler, J. Sorrell, D. Küchler and L. Sehrer for assistance during in vivo pharmacological studies. At F. Hoffmann–La Roche Ltd., we thank A. Roeckel, A. Vandjour and E. Hainaut for assistance during in vivo pharmacological studies; M. Brecheisen, C. Richardson, G. Branellec and V. Ott for necropsy and immunohistological procedures; C. Apfel, C. Wohlgesinger and V. Griesser for bioanalytics; and M. Kapps, C. Flament, P. Schrag, C. Rapp, M.S. Gruyer, V. Dall′Asen, F. Schuler and M. Otteneder for assistance in pharmacokinetic studies. We thank M. Charron (Albert Einstein College of Medicine) for providing Gcgr−/− mice and Y. Seino (Kansai Electric Power Hospital) for providing Gipr−/− mice. Partial research funding was provided by Marcadia Biotech, which has been acquired by F. Hoffmann–La Roche Ltd., and by grants from the Deutsche Forschungsgesellschaft (DFG; TS226/1-1), Deutsches Zentrum für Diabetesforschung (DZD), EurOCHIP (FP-7-HEALTH-2009-241592), Helmholtz Alliance ICEMED–Imaging and Curing Environmental Metabolic Diseases (through the Initiative and Networking Fund of the Helmholtz Association) and the Canadian Institutes of Health Research (93749).

Author information




B.F. designed and performed in vitro, in vivo and ex vivo rodent experiments, synthesized and characterized compounds, analyzed and interpreted data, and co-wrote the manuscript. B.Y. designed, synthesized and characterized compounds, performed in vitro experiments, and analyzed and interpreted data. N.O. designed and led in vivo pharmacology and metabolism rodent studies and interpreted data. D.P.-T., P.T.P., K.M.H., J.E.C., D.S., R.J.S., C.C., D.J.D., E.S., A.K. and T.D.M. designed, supervised and performed in vivo experiments and interpreted data. L.Z. designed in vivo experiments and interpreted data. K.F. performed in vivo experiments. J.C. and D.L.S. designed, synthesized and characterized compounds. K.B. designed and synthesized compounds. S.U., W.R., C.H., E.S., K.C.-K. and A.K. designed and performed in vivo and ex vivo analyses in ZDF rats and interpreted data. J.F. performed liver histology and interpreted data. S.U. performed pancreas histology and interpreted data. C.H., A.K. and V.G. designed and performed in vitro experiments and interpreted data. S.B. led pharmacokinetic studies and interpreted data. R.D.D. and M.H.T. conceptualized, designed and interpreted all studies and wrote the manuscript together with B.F.

Corresponding authors

Correspondence to Brian Finan, Richard D DiMarchi or Matthias H Tschöp.

Ethics declarations

Competing interests

R.D.D. was a cofounder of Marcadia Biotech and Calibrium Biotech. M.H.T. currently serves as a scientific advisor to Calibrium Biotech and Bionorica Pharmaceuticals. D.J.D. has served as an advisor or consultant within the past 12 months to Arisaph Pharmaceuticals, Diartis Pharmaceuticals, Eli Lilly, Intarcia Therapeutics, Merck Research Laboratories, Novo Nordisk, NPS Pharmaceuticals, Receptos, Sanofi, Takeda and Transition Pharmaceuticals. Neither D.J.D. nor his family members hold stock directly or indirectly in any of these companies.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–6 and Supplementary Figures 1–8. (PDF 4903 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Finan, B., Yang, B., Ottaway, N. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 21, 27–36 (2015).

Download citation

Further reading


Quick links