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.

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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


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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.

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