Dyslipidemia, including hypercholesterolemia and hypertriglyceridemia, represents a hallmark of the metabolic syndrome and triggers a host of obesity-associated comorbidities.
Thyroid hormones powerfully influence systemic metabolism through multiple pathways, with profound effects on energy expenditure, fat oxidation, and cholesterol metabolism. However, when used as thyroid hormone treatment, adverse side effects occur, including increased heart rate, cardiac hypertrophy, muscle wasting, and reduced bone density. Until now, discovery of thyromimetics capable of separating lipid metabolism benefits from adverse cardiovascular effects has remained a desire. A pharmacological agent that lowers cholesterol, triglycerides, glucose, hepatic fat, and body weight would offer a transformative advancement for treatment of the metabolic syndrome that should decrease mortality risk from cardiovascular events.
Scientists around Brian Finan from the Institute for Diabetes and Obesity at the Helmholtz Diabetes Center at Helmholtz Zentrum München engineered chemical conjugates that deliver the desired activities of glucogen and thyroid Hormone within one molecule while at the same time the inherent harmful effects of each molecule are reduced.
Of the intense studies in mice that were treated with conjugated glucagon and T3 effects on body temperature regulation, the cardiovascular system and cardiopathology were studied in the German Mouse Clinic.
Summing up the scientists showed that glucagon-mediated selective delivery of thyroid hormone to the liver results in coordinated actions that synergize to correct hyperlipidemia, reverse hepatic steatosis, and lower body weight through liver- and fat-specific mechanisms. The liver-directed thyroid hormone action overrides the diabetogenic liability of local glucagon action resulting in a net improvement of glycemic control, while glucagon-mediated delivery spares adverse action of thyroid hormone, notably on the cardiovascular system.
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. Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell. 2016 Oct 20;167(3):843-857.e14. doi: 10.1016/j.cell.2016.09.014. Epub 2016 Oct 6.