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Cell. 2016 Oct 20;167(3):843-857.e14. doi: 10.1016/j.cell.2016.09.014. Epub 2016 Oct 6.

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

Author information

1
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
2
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
3
Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), École Normale Supérieure de Lyon, 69364 Lyon, France.
4
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
5
Molecular EXposomics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
6
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
7
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
8
Division of Endocrinology, Department of Internal Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
9
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
10
Institute of Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany.
11
Department of Pathology and Molecular Pathology, University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland.
12
Institute of Virology, Technische Universität München, 81675 Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
13
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2200 Copenhagen, Denmark.
14
Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
15
Department of Medicine, Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336, Munich, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance (MHA), 80336 Munich, Germany.
16
Department of Medicine, Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, 80336, Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands.
17
Comprehensive Diabetes Center and Department of Medicine-Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
18
Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany.
19
Calibrium LLC, Carmel, IN 46032, USA.
20
Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
21
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
22
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85353, Germany.
23
German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute for Diabetes and Regeneration, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg 85764, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der LMU, München 80336, Germany.
24
Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany. Electronic address: matthias.tschoep@helmholtz-muenchen.de.
25
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA. Electronic address: rdimarch@indiana.edu.

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:

NASH; co-agonist; conjugate; dyslipidemia; glucagon; obesity; polypharmacology; thyroid hormone

PMID:
27720451
DOI:
10.1016/j.cell.2016.09.014
[Indexed for MEDLINE]
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