Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T 3 . In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T 3 required for UCP1 expression. T 3 actions are mediated by thyroid hormone nuclear T 3 receptors (TR), TR␣ and TR␤. Studies in mice suggest that TR␤ is required for UCP1 induction, whereas TR␣ regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T 3 vs. specific TR␤1 and TR␣1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T 3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nM). GC-1 at low doses (0.2-10 nM) was less potent than T 3 , increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T 3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T 3 , GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T 3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The ␣1-and ␣2-adrenergic D2 responses increased using high T 3 doses. In summary, T 3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TR␤1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T 3 on TR␤1. (Endocrinology 151: 5074 -5083, 2010)

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