The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes
The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes
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DOI：
10.1210/en.2010-0533
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发表时间：
2010-10-01
期刊：
影响因子：
4.8
通讯作者：
Obregon, Maria-Jesus
中科院分区：
文献类型：
--
作者：
Martinez de Mena, Raquel;Scanlan, Thomas S.;Obregon, Maria-Jesus
当解偶联蛋白-1(UCP1)被肾上腺素激活并需要T-3时，棕色脂肪组织(BAT)的产热增加。在人类中，蝙蝠中UCP1的激活似乎与体重维持有关。BAT 2型脱碘酶(D2)对肾上腺素能药物的反应增加，产生表达UCP1所需的T-3。T-3的作用是由甲状腺激素核T-3受体、T-3受体α和T-3β介导的。在小鼠身上的研究表明，trβ是UCP1诱导所必需的，而trα调节体温和肾上腺素能敏感性。在本研究中，我们比较了T-3与特异受体受体β1和受体α1激动剂[GC-1和CO23]对培养的大鼠棕色脂肪细胞UCP1和D2肾上腺素能诱导的影响。T-3和GC-1对UCP1的促进作用相似，而CO23仅在高剂量(50 NM)时增加UCP1。低剂量(0.2-10 nM)的GC-1作用弱于T-3，增强肾上腺素能刺激的D2活性和mRNA。在较高剂量下，GC-1进一步刺激，而T-3抑制D2活性，但不抑制D2mRNA，提示转录后效应。CO23对D2活性没有影响，但增加了D2mRNA的表达。T-3、GC-1或CO23单独作用不能增加UCP1或D2mRNA的表达。高T-3剂量缩短D2半衰期，增加D2通过蛋白酶体的周转，而GC-1不改变D2的稳定性。随着T-3剂量的增加，α1和α2肾上腺素能D2反应增加。总而言之，T-3主要通过trβ1亚型增加UCP1和D2表达的肾上腺素能刺激，在棕色脂肪细胞中，由于T-3对trβ1的作用，D2受到保护，使其免于降解。
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 alpha and TR beta. Studies in mice suggest that TR beta is required for UCP1 induction, whereas TR alpha regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T-3 vs. specific TR beta 1 and TR alpha 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 alpha 1- and alpha 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 beta 1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T-3 on TR beta 1. (Endocrinology 151: 5074-5083, 2010)