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Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic Impact for metabolic disease.
Cell 167, 843-857.e14 (2016)
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nash ; Co-agonist ; Conjugate ; Dyslipidemia ; Glucagon ; Obesity ; Polypharmacology ; Thyroid Hormone; Growth-factor 21; Receptor-beta Agonist; Fatty Liver-disease; Fgf21 In-vivo; Brown Fat; Adipose-tissue; Body-weight; Activation; Protects; Obesity
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 167, Heft: 3, Seiten: 843-857.e14 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Begutachtungsstatus peer-reviewed