CBBM Researchers Uncover Time-Dependent Effects of Thyroid Hormones on Liver Metabolism

Hypothyroidism, characterized by reduced thyroid hormone (TH) production, leads to multiple metabolic issues, including hypothermia, fatigue, weight gain, dry skin, and hair loss. Among various impacted organs, the liver is notably affected, with low TH levels increasing the susceptibility for fatty liver disease.

Considering that liver metabolism shows strong variations over the course of the day, surprisingly little is known about the temporal effects of low or high thyroid state. To address this gap, researchers from the Institute of Neurobiology and the Institute of Endocrinology and Diabetes at the Center of Brain, Behavior, and Metabolism (CBBM) studied the liver symptoms of hypothyroidism in mice. They found that mice with low TH levels showed a marked decrease in metabolic activity and body temperature. In contrast, the effects of hypothyroidism on liver physiology were subtle and much less pronounced when compared to high-TH effects. Prof Oster, senior author of the study, stresses that these findings indicate that the liver is a low TH action organ, thus being less responsive to a further decrease in TH levels.

The authors developed bioinformatic tools to discover that thyroid state influences liver biology in a time-of-day-dependent manner. In this way, they identified several novel TH-affected biological processes important for liver metabolism. Again, the liver’s response across the day was smaller in hypo- compared to hyperthyroid mice, which aligns with previous findings.

Dr. de Assis, the study's primary author, emphasizes the significance of considering time in metabolic studies. “Our temporal analysis is far superior to standard approaches neglecting time of day, and it is easily applicable to other tissues”, he states. The findings reinforce the necessity for further investigation to understand the intricate relationship between thyroid hormones, liver function, and time.

The study was published in January 2024 in Scientific Reports (https://doi.org/10.1038/s41598-023-50374-z) as part of the Collaborative Research Center "LocoTact”, funded by the German Research Foundation (DFG).

Thyroid hormones in pregnant women control brown adipose tissue in offspring

Brown adipose tissue (BAT) is a tissue that is utilized in babies to maintain body temperature. In adults, BAT is increasingly drawing the attention of researchers, especially in the context of obesity-related diseases, such as type 2 diabetes. Activating BAT could represent a promising therapeutic pathway to achieve metabolic improvement in the fight against the obesity pandemic. Researchers at the "Center of Brain, Behavior and Metabolism" (CBBM) at the University of Lübeck have now deciphered a mechanism involved in the activation of BAT. The research team led by Prof. Jens Mittag, head of the Institute of Endocrinology and Diabetes at the University of Lübeck, found that thyroid hormones of the mother during pregnancy had an influence on the later activity of the BAT of the offspring. The study was published in the journal Nature Communications.

BAT is currently being intensively researched in the context of obesity and type 2 diabetes, as it can burn fat and release it as heat. Activation of this tissue is therefore promised to improve metabolism and provide a new therapeutic target in the fight against the obesity pandemic. It has recently been shown that lean people often have more brown fat than obese people. However, it is still unclear why the activity of this tissue varies between individuals. Here, a research team of the Institute of Endocrinology and Diabetes at the CBBM has obtained first important evidence to solve this puzzle with the help of a mouse model.

"The key to brown adipose tissue activity seems to originate in the mother," reports Dr Rebecca Ölkrug, first author of the study. "Mothers with high thyroid hormone levels during pregnancy had offspring with more active brown adipose tissue, while genetic blockade of the beta-thyroid hormone receptor in the pregnant mice triggered the opposite effect. "By analyzing maternal blood at the CBBM Bioanalytic Core Facility, the researchers were also able to identify a possible molecular mechanism: Choline, an important nutrient for pregnant women, is directly regulated by maternal thyroid hormones.

"Our study underlines the high significance of the mother's hormonal situation for the offspring," explains Prof. Jens Mittag, last author of the study. "Unfortunately, in contrast to gestational diabetes, the thyroid is still frequently forgotten in pregnant women. Yet the necessary clinical tests are easy to perform, and there are specific reference values and treatment guidelines from, for example, the European Thyroid Society for pregnancy."

Oelkrug, R., Harder, L., Pedaran, M. et al. Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring. Nat Commun 14, 6742 (2023). https://doi.org/10.1038/s41467-023-42425-w