Ubiquitin C‐terminal hydrolase‐L3‐knockout mice are resistant to diet‐induced obesity and show increased activation of AMP‐activated protein kinase in skeletal muscle
Ubiquitin C‐terminal hydrolase‐L3‐knockout mice are resistant to diet‐induced obesity and show increased activation of AMP‐activated protein kinase in skeletal muscle
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DOI：
10.1096/fj.09-132217
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发表时间：
2009-12
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影响因子：
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通讯作者：
Rieko Setsuie;Mari Suzuki;Tomohiro Kabuta;H. Fujita;S. Miura;N. Ichihara;Daisuke Yamada;Yu-Lai Wang;O. Ezaki;Yasuyuki Suzuki;K. Wada
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文献类型：
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作者：
Rieko Setsuie;Mari Suzuki;Tomohiro Kabuta;H. Fujita;S. Miura;N. Ichihara;Daisuke Yamada;Yu-Lai Wang;O. Ezaki;Yasuyuki Suzuki;K. Wada
肥胖是由于全身能量平衡失调造成的。尽管泛素系统参与了许多细胞过程，但它对体内能量平衡的贡献仍然知之甚少。在这里，我们发现泛素C末端水解酶(UCH)-L3是脱泛素化酶之一，在代谢调节中起着重要作用。Uchl3−/−小鼠的脂肪组织质量减少，并能抵抗高脂饮食诱导的肥胖和胰岛素抵抗。同时给予正常饮食和高脂饮食的Uch13−/−小鼠，由于脂肪组织质量的减少，全身能量消耗增加。据报道，骨骼肌中AMP激活的蛋白激酶(AMPK)的激活增加了脂肪酸的β氧化，导致全身能量消耗的增加。在Uch13-β小鼠的骨骼肌中，一致地观察到AMPK的激活和脂肪酸的−/−-氧化增加。来自Uch13−/−小鼠的小鼠胚胎成纤维细胞也显示AMPK的激活增加，这表明Uch-L3参与了AMPK的细胞自主下调。这些结果表明，UCH-L3在调节AMPK活性和全身能量代谢方面发挥了作用。-Setsuie，R.，Suzuki，M.，Kabuta，T.，Fu-jita，H.，Miura，S.，Ichihara，N.，Yamada，D.，Wang，Y.-L.，Ezaki，O.，Suzuki，Y.，Wada，K.Ubiquitin C-末端水解酶-L3-基因敲除小鼠对饮食诱导的肥胖具有抵抗力，并显示骨骼肌中AMP激活的蛋白激酶活性增加。FASE B J.23,4148-4157(2009)。Www.fasebj.org
Obesity results from the dysregulation of energy balance throughout the entire body. Although the ubiquitin system participates in many cellular pro‐ cesses, its contribution to the balance of energy in the body remains poorly understood. Here, we show that ubiquitin C‐terminal hydrolase (UCH)‐L3, one of the deubiquitinating enzymes, contributes to the regulation of metabolism. Uchl3−/− mice displayed a reduction of adipose tissue mass and were protected against high‐fat diet (HFD)‐induced obesity and insulin resistance. Uchl3−/− mice given both a normal chow and an HFD had an increased whole‐body energy expenditure ac‐ counting for the reduction of adipose tissue mass. Activation of AMP‐activated protein kinase (AMPK) in skeletal muscle has been reported to increase fatty acid β‐oxidation, leading to the elevation of the whole‐body energy expenditure. Consistently, increased activation of AMPK and fatty acid β‐oxidation was observed in skeletal muscle of Uchl3−/− mice. Mouse embryonic fibroblasts derived from Uchl3−/− mice also showed increased activation of AMPK, indicating that UCH‐L3 is involved in a cell‐autonomous down‐regulation of AMPK. These results suggest a role for UCH‐L3 in the regulation of AMPK activity and whole‐body energy metabolism.—Setsuie, R., Suzuki, M., Kabuta, T., Fu‐ jita, H., Miura, S., Ichihara, N., Yamada, D., Wang, Y.‐L., Ezaki, O., Suzuki, Y., Wada, K. Ubiquitin C‐ terminal hydrolase‐L3‐knockout mice are resistant to diet‐induced obesity and show increased activation of AMP‐activated protein kinase in skeletal muscle. FASEB J. 23, 4148‐4157 (2009). www.fasebj.org