The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations

Abstract

Objective: Thyroid hormones regulate cardiovascular functions and energy homeostasis including thermogenesis through binding to nuclear thyroid hormone receptors. The thyroid hormone analogue 3,3',5-triiodothyroacetic acid (TRIAC) has recently emerged as a therapeutic candidate for thyroid hormone transporter deficiencies (Allan-Herndon-Dudley Syndrome) or thyroid hormone resistance β. Although TRIAC shows promise for these conditions, a comprehensive characterization focussing on heart and body temperature regulation has not been systematically performed in mice. Methods: As this knowledge is critical for determining its safety profile and therapeutic advantages over conventional thyroid hormone therapy, we administered TRIAC to wild-type mice for 14 days and assessed molecular (Realtime PCR, Western Blot, Immunoassays) and physiological responses (Infrared Thermography, Blood Pressure). Results: TRIAC treatment reduced circulating thyroxine levels and induced robust upregulation of hepatic thyroid hormone-responsive genes including Dio1 and Me1, demonstrating classical thyromimetic activity. However, cardiovascular analysis revealed normal blood pressure and heart rate, and no signs of cardiac hypertrophy despite specific molecular changes in cardiac gene expression. On the metabolic level, we surprisingly did not observe any effect on brown fat thermogenesis or body temperature, while in muscle Ucp3 and Gpd2 were reduced. Conclusions: Taken together, our comparative in vivo analysis demonstrates variable TRIAC responsiveness across tissues. Under defined conditions, the drug produces defined metabolic responses while avoiding classical hyperthyroid manifestations such as tachycardia or hyperthermia, thus supporting its potential therapeutic use in thyroid hormone resistance conditions.