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A T3 tactic
MUNICH, Germany--High levels of fat are tied to a host of conditions and health issues, including obesity, diabetes, atherosclerosis (accumulation of fat and cholesterol in the arteries) and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). According to the American Liver Foundation, approximately 20 percent of Americans are thought to have fatty livers, and primary liver cancer is on the rise, with some 21,000 Americans diagnosed every year.
And that's hardly the only country facing this issue; the British Society of Gastroenterology reports that roughly 33 percent of the U.K. population has NAFLD, with 2 to 5 percent diagnosed with NASH. At present, the Society notes, “it is now the commonest cause of liver disease in the West and accounts for a growing proportion of patients undergoing liver transplantation (15 to 20 percent).” New methods for helping people to better clear fat from the body to prevent buildup in arteries and the liver are greatly needed, and some of the latest work from an international team might be the groundwork for a new option.
The team in question has developed a “smart drug” that enters the liver by piggybacking off a common hormone produced in the pancreas. The results were published in Cell in a paper titled “Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.” The work was led by Prof. Matthias Tschöp, chair of Metabolic Diseases at the Technical University of Munich (TUM) and director of the Institute for Diabetes at Helmholtz Zentrum München; Richard diMarchi of Indiana University; and Timo Müller of Helmholtz Zentrum München.
The two hormones featured in this work are T3 and glucagon. T3 (triiodothyronine) is one of the body's thyroid hormones, which play significant parts in maintaining metabolism in the body. When the body's levels of T3 are higher than usual, it can be a sign of liver disease or an overactive thyroid gland, as in the case of Graves disease. According to Brian Finan, the first author of this work, “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.” Glucagon is produced by alpha cells in the islets of Langerhans in the pancreas, and play a role in helping the body regulate glucose levels and the use of glucose and fats, according to Diabetes.co.uk. When it is released in the body, it stimulates the liver to break down glycogen (which is released in the blood as glucose), activates gluconeogenesis (coversion of amino acids into glucose) and turns stored fat like triglycerides into fatty acids for cellular fuel.
“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,” Christoffer Clemmensen, who led several of the experiments for this work, explained in a press release. “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 combined glucagon/T3 molecule was found to deliver the T3 selectively to the liver, which led to better cholesterol metabolism in diet-induced obese mice in just a few days. The molecule also helped to decrease body weight, correct non-alcoholic fatty liver disease and improve glucose metabolism without any negative effects. When the team tested this approach in mice without the glucagon receptor or without the thyroid hormone receptor in only the liver, no metabolic improvement was seen, which seems to imply that its signal specificity is unique to the liver.
As noted in the paper's abstract, “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.” Specifically, this approach was found to correct dyslipidemia, obesity and hyperglycemia in diet-induced obesity mice, and to improve NASH and atherosclerosis in preclinical disease models.
The next part of this research, according to diMarchi, is “to see whether this drug candidate will reach the same level of targeted tissue-selectivity in clinical studies.” Based on that, and whether it proves safe and effective in humans, “then this particular ‘smart’ drug design may indeed offer perspectives for metabolic precision medicine,” Tschöp added.