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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    & Fat: an evolving issue. Dis. Model. Mech. 5, 569–573 (2012).

  2. 2.

    , , & The unrelenting fall of the pharmacological treatment of obesity. Endocrine 44, 598–609 (2013).

  3. 3.

    , & Anti-obesity drugs: past, present and future. Dis. Model. Mech. 5, 621–626 (2012).

  4. 4.

    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).

  5. 5.

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

  6. 6.

    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).

  7. 7.

    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).

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

    , , & GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7, 507–516 (2011).

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    , , & Optimization of the native glucagon sequence for medicinal purposes. J. Diabetes Sci. Technol. 4, 1322–1331 (2010).

  19. 19.

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

  20. 20.

    , , & Functional GIP receptors are present on adipocytes. Endocrinology 139, 4004–4007 (1998).

  21. 21.

    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).

  22. 22.

    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).

  23. 23.

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

  24. 24.

    , , , & 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).

  25. 25.

    , , & 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).

  26. 26.

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

  27. 27.

    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).

  28. 28.

    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).

  29. 29.

    & 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).

  30. 30.

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

  31. 31.

    , , & Oxyntomodulin increases intrinsic heart rate through the glucagon receptor. Physiol. Rep. 1, e00112 (2013).

  32. 32.

    , , & 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).

  33. 33.

    , , & Gastrointestinal hormones and bariatric surgery-induced weight loss. Obesity (Silver Spring) 21, 1093–1103 (2013).

  34. 34.

    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).

  35. 35.

    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).

  36. 36.

    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).

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

Author notes

    • Brian Finan
    •  & Bin Yang

    These authors contributed equally to this work.


  1. Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

    • Brian Finan
    • , Christoffer Clemmensen
    • , Katrin Fischer
    • , Paul T Pfluger
    • , Timo D Müller
    •  & Matthias H Tschöp
  2. Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.

    • Brian Finan
    • , Christoffer Clemmensen
    • , Katrin Fischer
    • , Paul T Pfluger
    • , Timo D Müller
    •  & Matthias H Tschöp
  3. Department of Chemistry, Indiana University, Bloomington, Indiana, USA.

    • Brian Finan
    • , Bin Yang
    • , David L Smiley
    • , Tao Ma
    • , Joe Chabenne
    • , Vasily Gelfanov
    •  & Richard D DiMarchi
  4. Marcadia Biotech, Carmel, Indiana, USA.

    • Bin Yang
    •  & Lianshan Zhang
  5. Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

    • Nickki Ottaway
    • , Darleen Sandoval
    • , Randy J Seeley
    •  & Diego Perez-Tilve
  6. Research Center, Beijing Hanmi Pharm., Beijing, China.

    • Tao Ma
  7. AIT Laboratories, Indianapolis, Indiana, USA.

    • Joe Chabenne
  8. Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Kirk M Habegger
  9. Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

    • Jonathan E Campbell
    •  & Daniel J Drucker
  10. Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

    • Konrad Bleicher
    • , Sabine Uhles
    • , William Riboulet
    • , Jürgen Funk
    • , Cornelia Hertel
    • , Sara Belli
    • , Elena Sebokova
    • , Karin Conde-Knape
    •  & Anish Konkar


  1. Search for Brian Finan in:

  2. Search for Bin Yang in:

  3. Search for Nickki Ottaway in:

  4. Search for David L Smiley in:

  5. Search for Tao Ma in:

  6. Search for Christoffer Clemmensen in:

  7. Search for Joe Chabenne in:

  8. Search for Lianshan Zhang in:

  9. Search for Kirk M Habegger in:

  10. Search for Katrin Fischer in:

  11. Search for Jonathan E Campbell in:

  12. Search for Darleen Sandoval in:

  13. Search for Randy J Seeley in:

  14. Search for Konrad Bleicher in:

  15. Search for Sabine Uhles in:

  16. Search for William Riboulet in:

  17. Search for Jürgen Funk in:

  18. Search for Cornelia Hertel in:

  19. Search for Sara Belli in:

  20. Search for Elena Sebokova in:

  21. Search for Karin Conde-Knape in:

  22. Search for Anish Konkar in:

  23. Search for Daniel J Drucker in:

  24. Search for Vasily Gelfanov in:

  25. Search for Paul T Pfluger in:

  26. Search for Timo D Müller in:

  27. Search for Diego Perez-Tilve in:

  28. Search for Richard D DiMarchi in:

  29. Search for Matthias H Tschöp in:


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.

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.

Corresponding authors

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

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Results, Supplementary Tables 1–6 and Supplementary Figures 1–8.

About this article

Publication history





Further reading Further reading