Priority Programme: THYROID TRANS ACT
Translation of Thyroid Hormone Actions beyond Classical Concepts

Development of a „smart drug“ to treat metabolic complication of obesity by transport T3 exclusively in the liver and brown fat by the group of Matthias Tschöp and Timo Müller together with two Thyroid Trans Act partners (Köhrle and Biebermann)

Researchers Helmholtz Zentrum München (HMGU) and Technische Universität München (TUM), Germany have developed a ‘smart’ drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone.

Smart drug clears fat from liver and blood

The constant rise in obesity and diabetes represents a major burden of our society. Fatty liver and atherosclerosis are frequent consequences of these metabolic diseases, but an efficient and safe medicine, which would reverse obesity, insulin resistance, fatty liver and atherosclerosis remains a major scientific challenge of global priority. An international team led by metabolism experts Matthias Tschöp (Technische Universität Müchen), Richard diMarchi (Indiana University) and Timo Müller (Helmholtz Center München) report in the current issue of the journal ‘Cell’ that liver-specific delivery of the thyroid hormone T3 using glucagon corrects obesity, glucose intolerance, fatty liver disease and atherosclerosis without causing adverse effects in other tissues. “While the ability of T3 to lower cholesterol is known for centuries, deleterious effects, in particular on the skeleton and the cardiovascular system, do so far limit its medicinal utility”, says Brian Finan, the first author of the manuscript.  

Toward precision medicines of the future 

“Part of our trick is, that we use the pancreatic hormone glucagon as a vehicle to deliver thyroid hormone only into cells carrying a glucagon receptor”, says Christoffer Clemmensen, who led several of the key experiments.  He explains: “Since there are lots of glucagon receptors in the liver, but almost none in heart or bone, our molecule concentrates thyroid hormone action to the liver while keeping it away from places where it would be harmful”.. “The next task is to see whether this drug candidate will reach the same level of targeted tissue-selectivity in clinical studies”, says diMarchi. “If the molecule shows equal efficacy and safety in humans, then this particular ‘smart’ drug design may indeed offer perspectives for metabolic precision medicine”, summarizes Tschöp.

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