Figure 2.

Overview of thyroid hormone (TH) production, transport, activity and regulation. The thyroid hormone signaling pathway involves a complex interplay between TH synthesis, transport, signal transduction, and catabolism. TH is synthesized within the hypothalamus-pituitary-thyroid (HPT) axis where the pituitary is stimulated to release thyroid stimulating hormone (TSH) by corticotropin releasing factor (CRF) from the hypothalamus. TSH induces the production of thyroxine (T₄) and, in lesser amounts, triiodothyronine (T₃) from the thyroid gland. The production of TH self-regulates through a negative feedback loop that inhibits further CRF and TSH production. TH travels through the blood via transporter proteins to peripheral tissues where it is imported into target cells. Here, T₄ is converted to T₃ through deiodinases (DIO), although T₄ can bind to receptors as well. Binding of THs to TH nuclear receptors (TR) leads to the activation of TH response genes. This change in transcript abundance results in downstream proteomic and metabolomic responses that produce the phenotypic changes resulting from the TH signal. The TH signal is also regulated within the cell by catabolism that includes processes such as sulfation, glucuronidation and deiodination.