A normal thyroid status is crucial for body temperature homeostasis, as thyroid hormone regulates both heat loss and conservation as well as heat production in thermogenic tissues. Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and an important target of thyroid hormone action. Thyroid hormone not only regulates the tissue’s sensitivity to sympathetic stimulation by norepinephrine, but also the expression of uncoupling protein 1, the key driver of BAT thermogenesis. Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling. This review summarizes the current knowledge on how thyroid hormone controls BAT thermogenesis, aiming to dissect the direct actions of the hormone in BAT and its indirect actions via the central nervous system, browning of white adipose tissue or heat loss over body surfaces. Of particular relevance is the apparent dose dependency of the observed effects, as we find that minor or moderate changes in thyroid hormone levels often have different effects as compared to high pharmacological doses. Moreover, we conclude that the more recent findings require a reevaluation of older studies, as key aspects such as heat loss or central BAT activation may not have received the necessary attention during the interpretation of these early findings. Finally, we provide a list of what we believe are the most relevant questions in the field that to date are still enigmatic and require further studies.
Sarah Christine Sentis, Rebecca Oelkrug, and Jens Mittag
Christin Krause, Martina Grohs, Alexander T El Gammal, Stefan Wolter, Hendrik Lehnert, Oliver Mann, Jens Mittag, and Henriette Kirchner
Hepatic thyroid hormone signaling has an important role in the development and progression of nonalcoholic steatohepatitis (NASH). While the systemic levels of thyroid hormone might remain stable, there is evidence that the intracellular signaling machinery consisting of transporters, deiodinases and receptors could be altered in NASH. However, clinical material from human liver biopsies of individuals with NASH has not been studied to date. In a cross-sectional study, we analyzed 85 liver biopsies from patients with different stages of NASH that underwent bariatric surgery. Using qPCR, we analyzed gene expression of thyroid hormone transporters NTCP (SLC10A1), MCT8 (SLC16A2) and OATP1C1 (SLCO1C1), thyroid hormone receptor α and β (THRA and THRB) and deiodinase type I, II and III (DIO1, DIO2, DIO3). The expression was correlated with serum TSH, triglyceride, HbA1c and NASH score and corrected for age or gender if required. While DIO2, DIO3 and SLCO1C1 were not expressed in human liver, we observed a significant negative correlation of THRB and DIO1 with age, and SLC16A2 with gender. THRB expression was also negatively associated with serum triglyceride levels and HbA1c. More importantly, its expression was inversely correlated with NASH score and further declined with age. Our data provide unique insight into the mRNA expression of thyroid hormone transporters, deiodinases and receptors in the human liver. The findings allow important conclusions on the intrahepatic mechanisms governing thyroid hormone action, indicating a possible tissue resistance to the circulating hormone in NASH, which becomes more prominent in advanced age.