Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2016-10, Vol.167 (3), p.843-857.e14

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Glucagon/T3 corrects dyslipidemia, obesity, and hyperglycemia in DIO mice•Glucagon/T3 improves NASH and atherosclerosis in preclinical disease models•Precise delivery of T3 to the liver mediates benefits and spares cardiac toxicity•Hepatic T3 action counteracts the diabetogenic liability of glucagon The therapeutic benefits of two hormones are maximized in a synthetic hybrid molecule that treats metabolic syndrome in mice by synergizing favorable effects and off-setting liabilities.