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

Brian Finan; Christoffer Clemmensen; 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; Maximilian Kleinert; 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

doi:10.1016/j.cell.2016.09.014

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

Brian Finan, Christoffer Clemmensen, 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 JastrochMaximilian Kleinert, 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

The August Krogh Section for Molecular Physiology

100 Citations (Scopus)

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.

Original language	English
Journal	Cell
Volume	167
Issue number	3
Pages (from-to)	843-857.e1-e14
Number of pages	29
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2016.09.014
Publication status	Published - 20 Oct 2016

Keywords

co-agonist
conjugate
dyslipidemia
glucagon
NASH
obesity
polypharmacology
thyroid hormone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., 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

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, vol. 167, no. 3, pp. 843-857.e1-e14. https://doi.org/10.1016/j.cell.2016.09.014

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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}",

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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 - 2016/10/20

Y1 - 2016/10/20

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

SN - 0092-8674

VL - 167

SP - 843-857.e1-e14

JO - Cell

JF - Cell

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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