Peroxisome proliferator-activated receptors γ and α mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression
Peroxisome proliferator-activated receptors γ and α mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression
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DOI：
10.1210/en.139.12.4920
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发表时间：
1998-12-01
期刊：
影响因子：
4.8
通讯作者：
Moller, DE
中科院分区：
文献类型：
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作者：
Kelly, LJ;Vicario, PP;Moller, DE
过氧化物酶体增殖体激活受体PPAR γ和PPAR α作为能量稳态和脂质代谢的调节因子已被提出。最近，三种不同的解偶联蛋白异构体，UCP-1， UCP-2和UCP-3，也被确定并与产热介质有关。在这里，我们研究了体内PPAR γ或PPAR α激活是否调节所有三种UCP亚型的表达。用PPAR γ[噻唑烷二酮（TZD）]或PPAR α (y -14643)激动剂治疗大鼠或瘦小鼠和db/db小鼠，然后在选定的表达UCP-1、UCP-2和UCP-3的组织中测量信使rna （mrna）。TZD处理（ad5075, 5 mg/kg d）使大鼠（14 d）棕色脂肪组织（BAT）库大小增加，并诱导各UCP mRNA的表达（UCP-1和UCP-2为对照水平的3倍，UCP-3为对照水平的2.5倍）。相比之下，白色脂肪组织和骨骼肌中UCP-2和UCP-3 mRNA水平不受影响。慢性（30天）低剂量（0.3 mg/kg）。TZD处理诱导BAT（2.5倍对照）UCP-1 mRNA和蛋白表达。相比之下，慢性TZD治疗（30 mg/kg d）抑制了BAT中UCP-1 mRNA（>80%）和蛋白（50%）的表达。这与进一步诱导UCP-2表达（>10倍）、脂泡大小增加、每个脂肪细胞中脂泡数量减少和脂肪细胞大小增加有关。TZD处理db/db小鼠（BRL 49653，每天10 mg/kg，持续10天）也能诱导BAT中UCP-1和UCP-3的表达（但没有UCP-2）。PPAR α存在于BAT和肝脏中。用WY-14643处理大鼠或db/db小鼠不影响BAT中UCP-1、-2或-3的表达。在db/db和瘦小鼠中，肝脏UCP-8 mRNA增加（4倍于对照水平），但在大鼠中未观察到这种影响。因此，体内PPAR γ激活可诱导BAT中UCP-1、-2和-3的表达；而慢性强烈的PPAR γ激活可能导致BAT呈现白色脂肪组织样表型，并增加UCP-8水平。小鼠PPAR α激活足以诱导肝脏UCP-2表达。
A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isoforms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 at 5 mg/kg day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control levels for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 and UCP-3 mRNA levels were not affected in white adipose tissue or skeletal muscle. Chronic (30 days) low-dose (0.3 mg/kg.day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chronic TZD treatment (30 mg/kg day) suppressed UCP-1 mRNA (>80%) and protein (50%) expression in BAT. This was associated with further induction of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyte, and an increase in the size of the adipocytes. TZD treatment of db/db mice (BRL 49653 at 10 mg/kg day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT, as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-8 mRNA was increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation can induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-intense PPAR gamma activation may cause BAT to assume white adipose tissue-like phenotype with increased UCP-8 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.