Indispensable role of mitochondrial UCP1 for antiobesity effect of β3-adrenergic stimulation
Indispensable role of mitochondrial UCP1 for antiobesity effect of β3-adrenergic stimulation
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DOI：
10.1152/ajpendo.00105.2005
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发表时间：
2006-05-01
影响因子：
5.1
通讯作者：
Saito, M
中科院分区：
文献类型：
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作者：
Inokuma, K;Okamatsu-Ogura, Y;Saito, M
线粒体解偶联蛋白-1(UCP1)被认为是冷暴露和自发性高吞噬过程中产热的关键分子，从而参与能量消耗和肥胖的自主神经调节。然而，UCP1基因敲除(KO)小鼠被报道为不耐冷，但出人意料的是，即使在过度吞噬后也没有肥胖，这意味着UCP1可能不参与肥胖的调节。已知用β(3)-肾上腺素能激动剂治疗肥胖动物可以增加脂肪动员，诱导UCP1，最终减少体内脂肪含量。为了获得UCP1在β(3)-肾上腺素能刺激的减肥作用中的直接证据，本研究将UCP1-KO和野生型(WT)小鼠按食堂饮食喂养8wk，然后给予β(3)-肾上腺素能激动剂CL-316,243(CL)或生理盐水2wk。一次注射CL可增加WT小鼠的全身耗氧量和棕色脂肪温度，但对KO小鼠没有影响，并引起WT和KO小鼠几乎相同的血浆游离脂肪酸反应。与实验室饮食相比，自助餐厅饮食的WT和KO小鼠的体重和白色脂肪垫重量增加相似。每天服用CL后，WT小鼠的白色脂肪垫重量和脂肪细胞的大小显著减少，而KO小鼠则没有。与WT小鼠相比，KO小鼠在棕色脂肪中表达的UCP2水平增加，而在白色脂肪中表达的UCP3水平降低。结论：β(3)-肾上腺素能刺激的减肥作用主要归因于UCP1，但不是UCP2和UCP3，而是依赖UCP1的白色脂肪组织释放的脂肪酸的降解。
Mitochondrial uncoupling protein-1 ( UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout ( KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with beta(3)-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of beta(3)-adrenergic stimulation, in the present study, UCP1-KO and wild-type ( WT) mice were fed on cafeteria diets for 8 wk and then given a beta(3)-adrenergic agonist, CL-316,243 ( CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of beta(3)-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.