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

Brian Finan | Zendy; Christoffer Clemmensen | Zendy; Zhimeng Zhu | Zendy; Kerstin Stemmer | Zendy; Karine Gauthier | Zendy; Luisa Müller | Zendy; Meri De Angelis | Zendy; Kristin Moreth | Zendy; Frauke Neff | Zendy; Diego Pérez–Tilve | Zendy; Katrin Fischer | Zendy; Dominik Lutter | Zendy; Miguel A. Sánchez-Garrido | Zendy; Peng Liu | Zendy; Jan Tuckermann | Zendy; Mohsen Malehmir | Zendy; Marc E. Healy | Zendy; Achim Weber | Zendy; Mathias Heikenwälder | Zendy; Martin Jastroch | Zendy; Maximilian Kleinert | Zendy; Sigrid Jall | Zendy; Sara J. Brandt | Zendy; Frédéric Flamant | Zendy; KarlWerner Schramm | Zendy; Heike Biebermann | Zendy; Yvonne Döring | Zendy; Christian Weber | Zendy; Kirk M. Habegger | Zendy; Michaela Keuper | Zendy; Vasily M. Gelfanov | Zendy; Fa Liu | Zendy; Josef Köhrle | Zendy; Jan Rozman | Zendy; Helmut Fuchs | Zendy; Valérie GailusDurner | Zendy; Martin Hrabé de Angelis | Zendy; Susanna M. Hofmann | Zendy; Bin Yang | Zendy; Matthias H. Tschöp | Zendy; Richard D. DiMarchi | Zendy; Timo D. Müller | Zendy

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

Author(s) -

Brian Finan,

Christoffer Clemmensen,

Zhimeng Zhu,

Kerstin Stemmer,

Karine Gauthier,

Luisa Müller,

Meri De Angelis,

Kristin Moreth,

Frauke Neff,

Diego Pérez–Tilve,

Katrin Fischer,

Dominik Lutter,

Miguel A. Sánchez-Garrido,

Peng Liu,

Jan Tuckermann,

Mohsen Malehmir,

Marc E. Healy,

Achim Weber,

Mathias Heikenwälder,

Martin Jastroch,

Maximilian Kleinert,

Sigrid Jall,

Sara J. Brandt,

Frédéric Flamant,

KarlWerner Schramm,

Heike Biebermann,

Yvonne Döring,

Christian Weber,

Kirk M. Habegger,

Michaela Keuper,

Vasily M. Gelfanov,

Fa Liu,

Josef Köhrle,

Jan Rozman,

Helmut Fuchs,

Valérie GailusDurner,

Martin Hrabé de Angelis,

Susanna M. Hofmann,

Bin Yang,

Matthias H. Tschöp,

Richard D. DiMarchi,

Timo D. Müller

Publication year - 2016

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2016.09.014

Subject(s) - glucagon , hormone , biology , steatohepatitis , endocrinology , hyperlipidemia , medicine , insulin , disease , type 2 diabetes , glucagon receptor , diabetes mellitus , fatty liver

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.

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