Mutational Screening of the Human Type II Deiodinase Gene

Introduction

Type II iodothyronine deiodinase (TIID) plays an important role in peripheral thyroid hormone metabolism. TIID catalyzes the conversion of thyroxine (T₄) to the active hormone 3,5,3’-triiodothyronine (T₃) by deiodination at the 5-prime position on the outer ring [1]. TIID is a selenoprotein expressed in fetal and adult brain, anterior pituitary gland, heart, and skeletal muscle, and also in brown adipose tissue (BAT) [2]. BAT is highly specialized for stimulated energy expenditure with a rich vascular supply, dense sympathetic innervation and numerous mitochondria [3]. Catecholamines activate the uncoupling of oxidative metabolism from ATP synthesis via the uncoupling protein-1 (UCP1). The dissipation of energy through the release of heat is further promoted by the chronic effect of norepinephrine on transcription of the UCP1 gene. T₃, resulting from local production in BAT via TIID, potentiates this effect of norepinephrine on UCP1 mRNA by 4 - 5-fold [4]. Cold exposure, one major stimulus of BAT thermogenesis, causes a 17-fold increase in TIID mRNA in rat BAT [2]. Although BAT plays a quantitatively limited role in humans, UCP1 mRNA can be detected in numerous adipose depots [5]. When stimulated by the sympathetic nervous system, even small quantities of BAT could significantly influence energy homeostasis. The expression of TIID mRNA in skeletal muscle [6] and the ability of T₃ to upregulate the human UCP3 gene in muscle tissue [7] suggests yet another mode by which alterations in local T₃ levels caused by TIID activity could influence energy expenditure. As with BAT, TIID expression in muscle cells is upregulated by β-adrenergic mechanisms and downregulated by thyroid hormones [8]. Taken together, these findings characterize TIID, localized on chromosome 14q24.3 [9], as a candidate gene for human obesity. Hence, our study was undertaken to identify possible mutations in the coding sequence of the TIID gene and assess their prevalence in obese compared to lean subjects.

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