title: Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.
abstract: Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Clemmensen
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Zhimeng
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), École Normale Supérieure de Lyon, 69364 Lyon, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Gauthier
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Müller
authors.affiliation: Molecular EXposomics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Meri
authors.initials: M
authors.lastname: De Angelis
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Moreth
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Lutter
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sánchez-Garrido
authors.affiliation: Institute of Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.affiliation: Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Malehmir
authors.affiliation: Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Healy
authors.affiliation: Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Virology, Technische Universität München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jastroch
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Jall
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Brandt
authors.affiliation: Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), École Normale Supérieure de Lyon, 69364 Lyon, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Flamant
authors.affiliation: Molecular EXposomics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
authors.forename: Karl-Werner
authors.initials: KW
authors.lastname: Schramm
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.affiliation: Department of Medicine, Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance (MHA), 80336 Munich, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.affiliation: Department of Medicine, Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336, Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine-Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.affiliation: Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Keuper
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.affiliation: Calibrium LLC, Carmel, IN 46032, USA.
authors.forename: Fa
authors.initials: F
authors.lastname: Liu
authors.affiliation: Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.affiliation: German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85353, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU, München 80336, Germany.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Hofmann
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address: matthias.tschoep@helmholtz-muenchen.de.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. Electronic address: rdimarch@indiana.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects; D002616:Chemical Engineering / Q000379:methods; D002784:Cholesterol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005934:Glucagon / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy*; D051379:Mice; D058990:Molecular Targeted Therapy; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy; D009765:Obesity / Q000188:drug therapy; D014284:Triiodothyronine / Q000009:adverse effects / Q000737:chemistry / Q000187:drug effects* / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; D014284:Triiodothyronine; D005934:Glucagon; D002784:Cholesterol
keywords: NASH; co-agonist; conjugate; dyslipidemia; glucagon; obesity; polypharmacology; thyroid hormone