Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts

Annunziata G. Cicatiello, Daniela Di Girolamo, Monica Dentice

Thyroid hormones (THs) are key determinants of cellular metabolism and regulate a variety of pathways that are involved in the metabolism of carbohydrates, lipids and proteins in several target tissues. Notably, hyperthyroidism induces a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, increased lipolysis and gluconeogenesis followed by weight loss, whereas hypothyroidism induces a hypo-metabolic state characterized by reduced energy expenditure, increased cholesterol levels, reduced lipolysis and gluconeogenesis followed by weight gain. Thyroid hormone is also a key regulator of mitochondria respiration and biogenesis. Besides mirroring systemic TH concentrations, the intracellular availability of TH is potently regulated in target cells by a mechanism of activation/inactivation catalyzed by three seleno-proteins: type 1 and type 2 iodothyronine deiodinase (D1 and D2) that convert the biologically inactive precursor thyroxine T4 into T3, and type 3 iodothyronine deiodinase (D3) that inactivates TH action. Thus, the pleiotropic effects of TH can fluctuate among tissues and strictly depend on the cell-autonomous action of the deiodinases. Here we review the mechanisms of TH action that mediate metabolic regulation. This review traces the critical impact of peripheral regulation of TH by the deiodinases on the pathways that regulate energy metabolism and the balance among energy intake, expenditure and storage in specific target tissues.