1. Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease
- Author
-
Kirk M. Habegger, Fa Liu, Dominik Lutter, Richard D. DiMarchi, Marc E. Healy, Maximilian Kleinert, Heike Biebermann, Yvonne Döring, Diego Perez-Tilve, Katrin Fischer, Luisa Müller, Peng Liu, Achim Weber, Susanna M. Hofmann, Christian Weber, Martin Jastroch, Frédéric Flamant, Miguel A. Sánchez-Garrido, Karl-Werner Schramm, Helmut Fuchs, Valerie Gailus-Durner, Brian Finan, Jan Rozman, Mohsen Malehmir, Sigrid Jall, Matthias H. Tschöp, Martin Hrabě de Angelis, Kerstin Stemmer, Josef Köhrle, Christoffer Clemmensen, Bin Yang, Meri De Angelis, Timo D. Müller, Sara J. Brandt, Zhimeng Zhu, Michaela Keuper, Vasily M. Gelfanov, Mathias Heikenwalder, Kristin Moreth, Frauke Neff, Jan Tuckermann, Karine Gauthier, German Center for Diabetes Research, Helmholtz-Zentrum München (HZM), Technische Universitat Munchen, Indiana University System, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), College of Medicine, University of Lagos, Universität Ulm - Ulm University [Ulm, Allemagne], University of Zurich, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Copenhagen = Københavns Universitet (KU), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Ludwig Maximilians University of Munich, German Center for Cardiovascular Research, Maastricht University [Maastricht], University of Alabama at Birmingham [ Birmingham] (UAB), Calibrium LLC, Klinikum der LMU, Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, RS: CARIM - R1.01 - Blood proteins & engineering, Maastricht University, and École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL)
- Subjects
0301 basic medicine ,obesity ,[SDV]Life Sciences [q-bio] ,MESH: Metabolic Diseases ,White adipose tissue ,Type 2 diabetes ,souris ,MESH: Triiodothyronine ,MESH: Drug Synergism ,MESH: Atherosclerosis ,0302 clinical medicine ,Drug Delivery Systems ,conjugate ,MESH: Cholesterol ,Non-alcoholic Fatty Liver Disease ,cardiovascular disease ,maladie cardiovasculaire ,Hyperlipidemia ,MESH: Molecular Targeted Therapy ,MESH: Obesity ,MESH: Animals ,Molecular Targeted Therapy ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,MESH: Glucagon ,Thyroid ,NASH ,Drug Synergism ,Chemical Engineering ,MESH: Bone and Bones ,3. Good health ,Drug Combinations ,obésité ,medicine.anatomical_structure ,Cholesterol ,Liver ,Triiodothyronine ,co-agonist ,MESH: Diabetes Mellitus, Type 2 ,medicine.medical_specialty ,mice ,MESH: Drug Delivery Systems ,030209 endocrinology & metabolism ,Biology ,Glucagon ,General Biochemistry, Genetics and Molecular Biology ,Bone and Bones ,Article ,03 medical and health sciences ,Metabolic Diseases ,Internal medicine ,medicine ,Animals ,Nash ,Co-agonist ,Conjugate ,Dyslipidemia ,Obesity ,Polypharmacology ,Thyroid Hormone ,Adverse effect ,MESH: Mice ,MESH: Drug Combinations ,polypharmacology ,hormone thyroïdienne ,dyslipidemie ,MESH: Non-alcoholic Fatty Liver Disease ,Body Weight ,dyslipidemia ,medicine.disease ,Atherosclerosis ,thyroid hormone ,MESH: Chemical Engineering ,MESH: Body Weight ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,glucagon ,Hyperglycemia ,Steatohepatitis ,MESH: Disease Models, Animal ,MESH: Hyperglycemia ,Hormone ,MESH: Liver - Abstract
International audience; 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 T3 actions 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 T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. 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.
- Published
- 2016
- Full Text
- View/download PDF