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 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.

• Authors: Brian Finan, Christoffer Clemmensen, Zhimeng Zhu, Kerstin Stemmer, Karine Gauthier, Luisa Müller, Meri De Angelis, Kristin Moreth, Frauke Neff, Diego Perez-Tilve, Katrin Fischer, Dominik Lutter, Miguel A Sánchez-Garrido, Peng Liu, Jan Tuckermann, Mohsen Malehmir, Marc E Healy, Achim Weber, Mathias Heikenwalder, Martin Jastroch, Maximilian Kleinert, Sigrid Jall, Sara Brandt, Frédéric Flamant, Karl-Werner Schramm, Heike Biebermann, Yvonne Döring, Christian Weber, Kirk M Habegger, Michaela Keuper, Vasily Gelfanov, Fa Liu, Josef Köhrle, Jan Rozman, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Susanna M Hofmann, Bin Yang, Matthias H Tschöp, Richard DiMarchi, Timo D Müller
• Journal: Cell (Cell) Vol. 167 Issue 3 Pg. 843-857.e14 (Oct 20 2016) ISSN: 1097-4172 [Electronic] United States
• PMID: 27720451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Drug Combinations
• Triiodothyronine
• Glucagon
• Cholesterol

Topics

• Animals
• Atherosclerosis (drug therapy)
• Body Weight (drug effects)
• Bone and Bones (drug effects)
• Chemical Engineering (methods)
• Cholesterol (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy)
• Disease Models, Animal
• Drug Combinations
• Drug Delivery Systems
• Drug Synergism
• Glucagon (adverse effects, chemistry, pharmacology, therapeutic use)
• Hyperglycemia (drug therapy)
• Liver (drug effects, metabolism)
• Metabolic Diseases (drug therapy)
• Mice
• Molecular Targeted Therapy
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Obesity (drug therapy)
• Triiodothyronine (adverse effects, chemistry, drug effects, pharmacology)