Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease
Open accessAbstract
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.
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The glucagon-T3 conjugate directed the hybrid molecule to the liver while sparing the cardiovascular system from adverse T3 effects.
“This property directed the hybrid molecule to the liver while sparing the cardiovascular system from adverse T3 effects.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [82]
Fusing T3 to a second hormone in a single molecular entity can obtain tissue-specific effects of T3.
“These findings support the strategy of fusing T3 to a second hormone in a single molecular entity in order to obtain tissue-specific effects of T3 (82).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [82]
Engineered chemical conjugates of glucagon and T3 deliver T3 to the liver.
“A unique strategy for directing T3 to the liver included engineered chemical conjugates of glucagon and T3, resulting in the delivery of T3 to the liver (the liver selectively expresses high levels of glucagon receptors) (82).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [82]
In mouse models of obesity, treatment with the glucagon-T3 conjugate corrected hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity.
“Treatment with this conjugate corrected hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in mouse models of obesity.”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [82]
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- Authors
- 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., 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.
- Affiliations
- Helmholtz Munich (DE)
- Indiana University Bloomington (US)
- École Normale Supérieure de Lyon (FR)
- Universität Ulm (DE)
- University of Zurich (CH)
- University of Copenhagen (DK)
- Charité – Universitätsmedizin Berlin (DE)
- German Centre for Cardiovascular Research (DE)
- Maastricht University (NL)
- University of Alabama at Birmingham (US)
- Corresponding author
- Tschöp, Matthias H.
- DiMarchi, Richard
- ORCID
- Finan, Brian
- Clemmensen, Christoffer
- Stemmer, Kerstin
- Gauthier, Karine
- Müller, Luisa
- Moreth, Kristin
- Fischer, Katrin
- Lutter, Dominik
- Liu, Peng
- Tuckermann, Jan
- Malehmir, Mohsen
- Healy, Marc E.
- Weber, Achim
- Jastroch, Martin
- Kleinert, Maximilian
- Jall, Sigrid
- 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
- Hofmann, Susanna M.
- Yang, Bin
- Tschöp, Matthias H.
- DiMarchi, Richard
- Müller, Timo D.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 167
- Issue
- 3
- Pages
- 843-857.e14
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2528971420
- Cited by
- 191
- References
- 52
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 15 · 2023: 20 · 2022: 18 · 2021: 18 · 2020: 17 · 2019: 22 · 2018: 28 · 2017: 31 · 2016: 4
- FWCI
- 22.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- HAL Portal Artxiker (Hindustan Aeronautics Limited (India)) (submittedVersion)
- HAL (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Alexander von Humboldt Foundation
- Helmholtz Association
- Deutsche Forschungsgemeinschaft (DFG-TS226/1-1 and DFG: SFB1123-A4, SFB1123-A1 and DFG: SFB1123-A4, DFG-BI893/2-2, DFG-BI893/8-1, SFB1123-A4)
- Alfred Benzon Foundation
- DFG/MCT8 Defizienz (GZ TS226/3-1 AOBJ:623001 [SPP1629])
- ANR
- European Union
- European Research Council (ERC AdG°249929)
- Schwerpunktprogram 1629 ThyroidTransAct (BI893/5-2)
- German Federal Ministry of Education and Research (01KX1012)
- German Center for Diabetes Research
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- glucagon, thyroid hormones, triiodothyronine, hormone synergy, metabolic disorders, hyperlipidemia, steatohepatitis, atherosclerosis, impaired glucose tolerance, obesity, type 2 diabetes, hepatic cholesterol metabolism, white adipose tissue browning, hepatocytes, adipocytes, diabetogenic effect, cardiovascular safety
- MeSH terms
- Animals, Body Weight, Bone and Bones, Chemical Engineering, Cholesterol, Diabetes Mellitus, Type 2, Disease Models, Animal, Drug Combinations, Drug Synergism, Glucagon, Hyperglycemia, Liver, Metabolic Diseases, Obesity, Triiodothyronine, Drug Delivery Systems, Atherosclerosis, Mice, Molecular Targeted Therapy, Non-alcoholic Fatty Liver Disease
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