Understanding the Hypothalamus-Pituitary-Thyroid Axis in Mct8 Deficiency

Abstract

Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain. In humans, inactivating mutations of the MCT8 gene (SLC16A2) are associated with severe forms of psychomotor retardation and abnormal TH serum levels (Allan-Herndon-Dudley syndrome). Surprisingly, Mct8 knockout (ko) mice do not exhibit overt neurological symptoms but fully replicate the unusual serum TH profile with highly increased serum T₃ in the presence of low serum T₄. In order to evaluate the underlying mechanisms for these abnormalities, TH transport and metabolism have been intensively studied in different tissues of Mct8 ko mice. Here, we summarize the observed changes within the hypothalamus-pituitary-thyroid axis that result in altered TH production and secretion. Although analysis of Mct8 ko mice has greatly expanded our knowledge, many open questions still remain to be addressed in order to define the tissue- and cell-specific role of this important TH transporter.