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

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

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 Mueller, Meri De Angelis, Kristin Moreth, Frauke Neff, Diego Perez-Tilve, Katrin Fischer, Dominik Lutter, Miguel A. Sanchez-Garrido, Peng Liu, Jan Tuckermann, Mohsen Malehmir, Marc E. Healy, Achim Weber, Mathias Heikenwalder, Martin JastrochMaximilian Kleinert, Sigrid Jall, Sara Brandt, Frederic Flamant, Karl-Werner Schramm, Heike Biebermann, Yvonne Doering, Christian Weber, Kirk M. Habegger, Michaela Keuper, Vasily Gelfanov, Fa Liu, Josef Koehrle, Jan Rozman, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Susanna M. Hofmann, Bin Yang, Matthias H. Tschoep^*, Richard DiMarchi^*, Timo D. Mueller

^*Corresponding author for this work

Biochemie

Research output: Contribution to journal › Article › Academic › peer-review

111 Citations (Web of Science)

Abstract

Glucagon and thyroid hormone (T-3) 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 T-3 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 T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 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
Pages (from-to)	843-857
Journal	Cell
Volume	167
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2016.09.014
Publication status	Published - 20 Oct 2016

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10.1016/j.cell.2016.09.014

Cite this

Finan, B., Clemmensen, C., Zhu, Z., Stemmer, K., Gauthier, K., Mueller, L., De Angelis, M., Moreth, K., Neff, F., Perez-Tilve, D., Fischer, K., Lutter, D., Sanchez-Garrido, M. A., Liu, P., Tuckermann, J., Malehmir, M., Healy, M. E., Weber, A., Heikenwalder, M., ... Mueller, T. D. (2016). Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell, 167(3), 843-857. https://doi.org/10.1016/j.cell.2016.09.014

@article{cb37ff1a209e450fb04b96d50ac2313e,

title = "Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease",

abstract = "Glucagon and thyroid hormone (T-3) 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 T-3 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 T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 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.",

author = "Brian Finan and Christoffer Clemmensen and Zhimeng Zhu and Kerstin Stemmer and Karine Gauthier and Luisa Mueller and {De Angelis}, Meri and Kristin Moreth and Frauke Neff and Diego Perez-Tilve and Katrin Fischer and Dominik Lutter and Sanchez-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 Frederic Flamant and Karl-Werner Schramm and Heike Biebermann and Yvonne Doering and Christian Weber and Habegger, {Kirk M.} and Michaela Keuper and Vasily Gelfanov and Fa Liu and Josef Koehrle and Jan Rozman and Helmut Fuchs and Valerie Gailus-Durner and {de Angelis}, {Martin Hrabe} and Hofmann, {Susanna M.} and Bin Yang and Tschoep, {Matthias H.} and Richard DiMarchi and Mueller, {Timo D.}",

year = "2016",

month = oct,

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doi = "10.1016/j.cell.2016.09.014",

language = "English",

volume = "167",

pages = "843--857",

journal = "Cell",

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Finan, B, Clemmensen, C, Zhu, Z, Stemmer, K, Gauthier, K, Mueller, L, De Angelis, M, Moreth, K, Neff, F, Perez-Tilve, D, Fischer, K, Lutter, D, Sanchez-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, K-W, Biebermann, H, Doering, Y, Weber, C, Habegger, KM, Keuper, M, Gelfanov, V, Liu, F, Koehrle, J, Rozman, J, Fuchs, H, Gailus-Durner, V, de Angelis, MH, Hofmann, SM, Yang, B, Tschoep, MH, DiMarchi, R & Mueller, TD 2016, 'Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease', Cell, vol. 167, no. 3, pp. 843-857. https://doi.org/10.1016/j.cell.2016.09.014

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 - Mueller, Luisa

AU - De Angelis, Meri

AU - Moreth, Kristin

AU - Neff, Frauke

AU - Perez-Tilve, Diego

AU - Fischer, Katrin

AU - Lutter, Dominik

AU - Sanchez-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, Frederic

AU - Schramm, Karl-Werner

AU - Biebermann, Heike

AU - Doering, Yvonne

AU - Weber, Christian

AU - Habegger, Kirk M.

AU - Keuper, Michaela

AU - Gelfanov, Vasily

AU - Liu, Fa

AU - Koehrle, Josef

AU - Rozman, Jan

AU - Fuchs, Helmut

AU - Gailus-Durner, Valerie

AU - de Angelis, Martin Hrabe

AU - Hofmann, Susanna M.

AU - Yang, Bin

AU - Tschoep, Matthias H.

AU - DiMarchi, Richard

AU - Mueller, Timo D.

PY - 2016/10/20

Y1 - 2016/10/20

N2 - Glucagon and thyroid hormone (T-3) 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 T-3 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 T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 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 (T-3) 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 T-3 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 T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 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.

U2 - 10.1016/j.cell.2016.09.014

DO - 10.1016/j.cell.2016.09.014

M3 - Article

C2 - 27720451

VL - 167

SP - 843

EP - 857

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -