Inactivation of type 3 Deiodinase Results in Life-Long Changes in Brown Adipose Tissue Transcriptome in the Male Mouse

: Adaptive thermogenesis in small mammals and infants takes place in the brown adipose tissue (BAT). Heat is produced via UCP1-mediated uncoupling between oxidation of energy substrates and ATP synthesis. Thyroid hormone signaling plays a role in this process. The deiodinases activate T4 to T3 (D2) or inactivate T4 and T3 to rT3 and T2 (D3), respectively. Using a mouse model with selective inactivation of Dio3 in BAT (flox-Dio3 x UCP1-cre = BAT-D3KO), we now show that knocking out D3 resulted in premature exposure of developing brown adipocytes (E16.5-18.5) to T3 signaling, leading to an earlier expression of key BAT genes, i.e. Cidea, Cox8b, Dio2, Ucp1, and Pgc1α. Adult BAT-D3KO mice exhibited increased expression of 1591 genes as assessed by RNA-seq, including 19 gene sets related to mitochondria, 8 related to fat, and 8 related to glucose homeostasis. The expression of 243 genes was changed by >1.5-fold, 36 of which play a role in metabolic/thermogenic processes. The BAT-D3KO mice weigh less and exhibit smaller white adipocyte area, but maintain normal energy expenditure at room temperature (22°C) and in the cold (4°C). They also defend their core temperature more effecttively and did not lose as much body weight when exposed to cold. We conclude that the coordinated actions of Dio3 in the embryonic BAT define the timing and intensity of T3 signaling during brown adipogenesis. Enhanced T3 signaling during BAT embryogenesis (Dio3 inactivation) results in selective life-long modifications in BAT transcriptome.