Regulation of TNFα converting enzyme activity in visceral adipose tissue of obese mice
Regulation of TNFα converting enzyme activity in visceral adipose tissue of obese mice
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DOI：
10.1016/j.bbrc.2012.12.086
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发表时间：
2013-01-25
影响因子：
3.1
通讯作者：
Araki, Eiichi
中科院分区：
文献类型：
--
作者：
Kawasaki, Shuji;Motoshima, Hiroyuki;Araki, Eiichi
肿瘤坏死因子α（TNFα）是一种促炎细胞因子，也是肥胖引起的胰岛素抵抗的主要介质之一。 TNF α 是通过 TNF α 转换酶 (TACE) 介导的跨膜前体 TNF α 前体裂解而产生的。 TACE 的抑制导致糖尿病动物的葡萄糖和胰岛素水平改善，这表明 TACE 活性在葡萄糖代谢中发挥着至关重要的作用。然而，胰岛素敏感组织中 TACE 活性的调节尚未完全确定。本研究旨在探讨 TACE 在肥胖发展早期对胰岛素敏感组织的影响。 C57BL6 小鼠喂食标准食物 (B6-SC) 或高脂肪/高蔗糖饮食 (B6-HF/HS)。 KK-Ay小鼠随意SC饲喂(Ay-AL)或饲喂减少量的SC(热量限制(CR)；Ay-CR)。作为Ay-AL的对照，使用随意SC喂养的KK小鼠(KK-AL)。与 B6-SC 和 KK-AL 相比，B6-HF/HS 和 Ay-AL 中内脏脂肪组织 (VAT) 的 TACE 活性显着升高，但肝脏或骨骼肌中的 TACE 活性没有显着升高。 B6-HF/HS 和 Ay-AL 的 VAT 中 JNK 和 p38MAPK（而非 ERK）的磷酸化也显着升高。与Ay-AL相比，Ay-CR显着降低VAT中的TACE、JNK和p38MAPK活性以及血清TNFα水平。相反，腹腔注射TNFα激活KK小鼠中VAT中的TACE、JNK和p38MAPK活性。总之，在肥胖的发展过程中，TACE活性仅在VAT中升高，而CR有效地降低了VAT中的TACE活性和TACE介导的pro-TNFα脱落。 (C) 2012 Elsevier Inc. 保留所有权利。
Tumor necrosis factor alpha (TNF alpha) is a pro-inflammatory cytokine and one of the major mediators of obesity-induced insulin resistance. TNF alpha is generated through TNF alpha converting enzyme (TACE)-mediated cleavage of the transmembrane precursor pro-TNF alpha. Inhibition of TACE resulted in the improvement in glucose and insulin levels in diabetic animals, suggesting a crucial role of TACE activity in glucose metabolism. However, the regulation of TACE activity in insulin-sensitive tissues has not been fully determined. This study aimed to investigate the impact of TACE in insulin-sensitive tissues in the early stage of the development of obesity. C57BL6 mice were fed standard chow (B6-SC) or high-fat/high-sucrose diet (B6-HF/HS). KK-Ay mice were fed SC ad libitum (Ay-AL) or fed reduced amounts of SC (caloric restriction (CR); Ay-CR). As control for Ay-AL, KK mice fed SC ad libitum (KK-AL) were used. TACE activity in visceral adipose tissue (VAT), but not in liver or skeletal muscle, was significantly elevated in B6-HF/HS and Ay-AL compared with B6-SC and KK-AL, respectively. Phosphorylation of JNK and p38MAPK, but not ERK, in VATs from B6-HF/HS and Ay-AL was also significantly elevated. Ay-CR showed significantly lower TACE, JNK and p38MAPK activities in VAT and serum TNF alpha level compared with those of Ay-AL In contrast, intraperitoneal injection of TNF alpha activated TACE, JNK and p38MAPK activities in VAT in KK mice. In conclusion, during the development of obesity, TACE activity is elevated only in VAT, and CR effectively reduced TACE activity and TACE-mediated pro-TNF alpha shedding in VAT. (C) 2012 Elsevier Inc. All rights reserved.