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

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Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. / 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, Valérie; Hrabě de Angelis, Martin; Hofmann, Susanna M; Yang, Bin; Tschöp, Matthias H; Dimarchi, Richard; Müller, Timo D.

I: Cell, Bind 167, Nr. 3, 2016, s. 843-857.e1-e14.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, MA, Liu, P, Tuckermann, J, Malehmir, M, Healy, ME, Weber, A, Heikenwalder, M, Jastroch, M, Kleinert, M, Jall, S, Brandt, S, Flamant, F, Schramm, KW, Biebermann, H, Döring, Y, Weber, C, Habegger, KM, Keuper, M, Gelfanov, V, Liu, F, Köhrle, J, Rozman, J, Fuchs, H, Gailus-Durner, V, Hrabě de Angelis, M, Hofmann, SM, Yang, B, Tschöp, MH, Dimarchi, R & Müller, TD 2016, 'Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease', Cell, bind 167, nr. 3, s. 843-857.e1-e14. https://doi.org/10.1016/j.cell.2016.09.014

APA

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., Malehmir, M., Healy, M. E., Weber, A., Heikenwalder, M., ... Müller, T. D. (2016). Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell, 167(3), 843-857.e1-e14. https://doi.org/10.1016/j.cell.2016.09.014

Vancouver

Finan B, Clemmensen C, Zhu Z, Stemmer K, Gauthier K, Müller L o.a. Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell. 2016;167(3):843-857.e1-e14. https://doi.org/10.1016/j.cell.2016.09.014

Author

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, Valérie ; Hrabě de Angelis, Martin ; Hofmann, Susanna M ; Yang, Bin ; Tschöp, Matthias H ; Dimarchi, Richard ; Müller, Timo D. / Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. I: Cell. 2016 ; Bind 167, Nr. 3. s. 843-857.e1-e14.

Bibtex

@article{bdabb5ea62724688adf662cc29fef2e2,
title = "Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease",
abstract = "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.",
keywords = "co-agonist, conjugate, dyslipidemia, glucagon, NASH, obesity, polypharmacology, thyroid hormone",
author = "Brian Finan and Christoffer Clemmensen and Zhimeng Zhu and Kerstin Stemmer and Karine Gauthier and Luisa M{\"u}ller and {De Angelis}, Meri and Kristin Moreth and Frauke Neff and Diego Perez-Tilve and Katrin Fischer and Dominik Lutter and S{\'a}nchez-Garrido, {Miguel A.} and Peng Liu and Jan Tuckermann and Mohsen Malehmir and Healy, {Marc E.} and Achim Weber and Mathias Heikenwalder and Martin Jastroch and Maximilian Kleinert and Sigrid Jall and Sara Brandt and Fr{\'e}d{\'e}ric Flamant and Schramm, {Karl Werner} and Heike Biebermann and Yvonne D{\"o}ring and Christian Weber and Habegger, {Kirk M} and Michaela Keuper and Vasily Gelfanov and Fa Liu and Josef K{\"o}hrle and Jan Rozman and Helmut Fuchs and Val{\'e}rie Gailus-Durner and {Hrab{\v e} de Angelis}, Martin and Hofmann, {Susanna M} and Bin Yang and Tsch{\"o}p, {Matthias H} and Richard Dimarchi and M{\"u}ller, {Timo D}",
note = "CURIS 2016 NEXS 400",
year = "2016",
doi = "10.1016/j.cell.2016.09.014",
language = "English",
volume = "167",
pages = "843--857.e1--e14",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease

AU - Finan, Brian

AU - Clemmensen, Christoffer

AU - Zhu, Zhimeng

AU - Stemmer, Kerstin

AU - Gauthier, Karine

AU - Müller, Luisa

AU - De Angelis, Meri

AU - Moreth, Kristin

AU - Neff, Frauke

AU - Perez-Tilve, Diego

AU - Fischer, Katrin

AU - Lutter, Dominik

AU - Sánchez-Garrido, Miguel A.

AU - Liu, Peng

AU - Tuckermann, Jan

AU - Malehmir, Mohsen

AU - Healy, Marc E.

AU - Weber, Achim

AU - Heikenwalder, Mathias

AU - Jastroch, Martin

AU - Kleinert, Maximilian

AU - Jall, Sigrid

AU - Brandt, Sara

AU - Flamant, Frédéric

AU - Schramm, Karl Werner

AU - Biebermann, Heike

AU - Döring, Yvonne

AU - Weber, Christian

AU - Habegger, Kirk M

AU - Keuper, Michaela

AU - Gelfanov, Vasily

AU - Liu, Fa

AU - Köhrle, Josef

AU - Rozman, Jan

AU - Fuchs, Helmut

AU - Gailus-Durner, Valérie

AU - Hrabě de Angelis, Martin

AU - Hofmann, Susanna M

AU - Yang, Bin

AU - Tschöp, Matthias H

AU - Dimarchi, Richard

AU - Müller, Timo D

N1 - CURIS 2016 NEXS 400

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - co-agonist

KW - conjugate

KW - dyslipidemia

KW - glucagon

KW - NASH

KW - obesity

KW - polypharmacology

KW - thyroid hormone

U2 - 10.1016/j.cell.2016.09.014

DO - 10.1016/j.cell.2016.09.014

M3 - Journal article

C2 - 27720451

VL - 167

SP - 843-857.e1-e14

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -

ID: 178892182