Iodothyronine Deiodinase - Biological Function

Biological Function

Deiodinase 1 both activates T₄ to produce T₃ and inactivates T₄. Besides its increased function in producing extrathyroid T₃ in patients with hyperthyroidism, its function is less well understood than D2 or D3 Deiodinase 2, located in the ER membrane, converts T₄ into T₃ and is a major source of the cytoplasmic T₃ pool. Deiodinase 3 prevents T₄ activation and inactivates T₃. D2 and D3 are important in homeostatic regulation in maintaining T₃ levels at the plasma and cellular levels. In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T₃, while in hypothyroidism D2 is upregulated and D3 is downregulated to increase cytoplasmic T₃ levels.

Serum T₃ levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T₃ to maintain homeostasis since T₃ and T₄ levels may vary by organ. Deiodinases also provide spatial and temporal developmental control of thyroid hormone levels. D3 levels are highest early in development and decrease over time, while D2 levels are high at moments of significant metamorphic change in tissues. Thus D2 enables production of sufficient T₃ at necessary time points while D3 may shield tissue from overexposure to T₃.

Deiodinase 2 also plays a significant role in thermogenesis in brown adipose tissue (BAT). In response to sympathetic stimulation, dropping temperature, or overfeeding BAT, increases oxidation of fatty acids and uncouples oxidative phosphorylation by UCP causing mitochondrial heat production. Deiodinase 2 increases during cold stress in BAT and increases intracellular T₃ levels. In D2 deficient models, shivering is a behavioral adaptation to the cold. However, heat production is much less efficient than uncoupling lipid oxidation.