Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Brian Finan
  • 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
  • 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
  • Valérie Gailus-Durner
  • Martin Hrabě de Angelis
  • Susanna M Hofmann
  • Bin Yang
  • Matthias H Tschöp
  • Richard Dimarchi
  • Timo D Müller

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.

Udgave nummer3
Sider (fra-til)843-857.e1-e14
Antal sider29
StatusUdgivet - 2016

Bibliografisk note

CURIS 2016 NEXS 400

ID: 178892182