The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.

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The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3,5-triiodothyronine (T3), the disruption of which (Dio2 ؊/؊ ) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2 ؊/؊ BAT sympathetic stimulation ϳ10-fold (normal ϳ4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor ␥ coactivator 1, increased well above the levels detected in the coldexposed wild-type animals. The sustained Dio2 ؊/؊ BAT adrenergic hyperresponse suppressed the three-to fourfold stimulation of BAT lipogenesis normally seen after 24 -48 h in the cold. Pharmacological suppression of lipogenesis with ␤␤-methyl-substituted ␣--dicarboxylic acids of C14 -C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2 ؊/؊ mice. A dequate quantities of thyroid hormone are required for the maintenance of basal energy expenditure (1,2) and are also critical for adjustments in energy homeostasis during acute exposure to cold, without which survival is not possible (3). These adjustments in nonshivering adaptive thermogenesis are initiated by an increase in the activity of the sympathetic nervous system (SNS). In human newborns and other small mammals, brown adipose tissue (BAT) is the main site of the sympathetic-mediated adaptive thermogenesis. During cold exposure, there is an acute ϳ50-fold increase in type 2 iodothyronine deiodinase (D2) activity in BAT that accelerates thyroxine (T4) to 3,3Ј,5-triiodothyronine (T3) conversion (4). This increases thyroid hormone receptor (TR) saturation and leads to intracellular thyrotoxicosis specifically in this tissue (5), which in turn increases adrenergic responsiveness (6 -8) in a feed-forward mechanism that allows BAT to produce heat in a sustainable manner.The current paradigm of thyroid-adrenergic synergism is based on the principle that hypothyroidism causes a generalized decrease in adrenergic responsiveness and, therefore, frustrates the homeostatic role of the SNS, including the stimulation of BAT (9,10). However, these studies are largely based on the hypothyroid animal as a model, which has serious limitations for this purpose. The reduced obligatory energy expenditure caused by systemic hypothyroidism leads to a generalized and gradual increase in sympathetic activity that, in the BAT, activates adaptive energy expenditure to sustain normal core temperature, even at room temperature (11). However, chronic norepi...