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Finan, B. ; Clemmensen, C. ; Zhu, Z.* ; Stemmer, K. ; Gauthier, K.* ; Müller, L. ; de Angelis, M. ; Moreth, K. ; Neff, F. ; Perez-Tilve, D.* ; Fischer, K. ; Lutter, D. ; Sánchez-Garrido, M.A. ; Liu, P.* ; Tuckermann, J.P.* ; Malehmir, M.* ; Healy, M.E.* ; Weber, A.* ; Heikenwälder, M.* ; Jastroch, M. ; Kleinert, M. ; Jall, S. ; Brandt, S. ; Flamant, F.* ; Schramm, K.-W. ; Biebermann, H.* ; Döring, Y.* ; Weber, C.* ; Habegger, K.M.* ; Keuper, M. ; Gelfanov, V.* ; Liu, F.* ; Köhrle, J.* ; Rozman, J. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Hofmann, S.M. ; Yang, B.* ; Tschöp, M.H. ; DiMarchi, R.* ; Müller, T.D.

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

Cell 167, 843-857.e14 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nash ; Co-agonist ; Conjugate ; Dyslipidemia ; Glucagon ; Obesity ; Polypharmacology ; Thyroid Hormone; Growth-factor 21; Receptor-beta Agonist; Fatty Liver-disease; Fgf21 In-vivo; Brown Fat; Adipose-tissue; Body-weight; Activation; Protects; Obesity
Language german
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 167, Issue: 3, Pages: 843-857.e14 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
PPM-MEX-Molecular EXposomics (MEX)
Institute of Pathology (PATH)
Institute of Experimental Genetics (IEG)
Institute of Diabetes and Regeneration Research (IDR)
POF-Topic(s) 30201 - Metabolic Health
30202 - Environmental Health
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease

90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
Environmental Sciences
Enabling and Novel Technologies
Genetics and Epidemiology
PSP Element(s) G-502200-001
G-509100-001
G-500300-001
G-500600-001
G-500692-001
G-502390-001
G-508400-002
G-501900-063
G-501900-022
DOI 10.1016/j.cell.2016.09.014
WOS ID WOS:000386344100028
Scopus ID 84993982751
Scopus ID 84992036608
PubMed ID 27720451
Erfassungsdatum 2016-10-12
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