Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease

Brian Finan, Christoffer Clemmensen, Zhimeng Zhu, Kerstin Stemmer, Karine Gauthier, Luisa Mueller, Meri De Angelis, Kristin Moreth, Frauke Neff, Diego Perez-Tilve, Katrin Fischer, Dominik Lutter, Miguel A. Sanchez-Garrido, Peng Liu, Jan Tuckermann, Mohsen Malehmir, Marc E. Healy, Achim Weber, Mathias Heikenwalder, Martin JastrochMaximilian Kleinert, Sigrid Jall, Sara Brandt, Frederic Flamant, Karl-Werner Schramm, Heike Biebermann, Yvonne Doering, Christian Weber, Kirk M. Habegger, Michaela Keuper, Vasily Gelfanov, Fa Liu, Josef Koehrle, Jan Rozman, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Susanna M. Hofmann, Bin Yang, Matthias H. Tschoep*, Richard DiMarchi*, Timo D. Mueller

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

111 Citations (Web of Science)

Abstract

Glucagon and thyroid hormone (T-3) 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 T-3 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 T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 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.
Original languageEnglish
Pages (from-to)843-857
JournalCell
Volume167
Issue number3
DOIs
Publication statusPublished - 20 Oct 2016

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