title: A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents.
abstract: 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.
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany. [3] Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: Brian
authors.identifier: 0000000264670447
authors.initials: B
authors.lastname: Finan
authors.affiliation: 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] Marcadia Biotech, Carmel, Indiana, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Smiley
authors.affiliation: 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] Research Center, Beijing Hanmi Pharm., Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Clemmensen
authors.affiliation: 1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] AIT Laboratories, Indianapolis, Indiana, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Chabenne
authors.affiliation: Marcadia Biotech, Carmel, Indiana, USA.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Comprehensive Diabetes Center, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Campbell
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Darleen
authors.initials: D
authors.lastname: Sandoval
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Konrad
authors.initials: K
authors.lastname: Bleicher
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Uhles
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: William
authors.initials: W
authors.lastname: Riboulet
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Funk
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hertel
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Belli
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Anish
authors.initials: A
authors.lastname: Konkar
authors.affiliation: Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.affiliation: 1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000235:genetics; D048909:Diabetes Complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D012377:Rodentia
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor