The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold du ring cold stress only in brown adipose tissue (BAT). Here we report that de spite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-expo sed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypot hermic due to impaired BAT thermogenesis and survive by compensatory shiver ing with consequent acute weight loss. This occurs despite normal basal mit ochondrial uncoupling protein 1 (UCP1) concentration. In Dio2(-/-) brown ad ipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced incre ases in lipolysis, UCP1 mRNA, and O-2 consumption are all reduced due to im paired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies sugg est that UCP1 is primarily dependent on thyroid hormone receptor beta (TR b eta) while the normal sympathetic response of brown adipocytes requires TR alpha. Intracellularly generated T3 may be required to saturate the TR alph a, which has an approximately fourfold lower T3-binding affinity than does TR beta. Thus, D2 is an essential component in the thyroid-sympathetic syne rgism required for thermal homeostasis in small mammals.