Metabolic consequences of ENPP1 overexpression in adipose tissue
Metabolic consequences of ENPP1 overexpression in adipose tissue
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DOI：
10.1152/ajpendo.00087.2011
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发表时间：
2011-11-01
影响因子：
5.1
通讯作者：
Abate, Nicola
中科院分区：
文献类型：
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作者：
Pan, Wentong;Ciociola, Ester;Abate, Nicola
Pan W、Ciociola E、Saraf M、Tumurbaatar B、Tuvdendorj D、Prasad S、Chandalia M、Abate N。脂肪组织中 ENPP1 过度表达的代谢后果。 Am J Physiol Endocrinol Metab 301：E901-E911，2011。首次发表于 2011 年 8 月 2 日； doi: 10.1152/ajpendo.00087.2011.-外核苷酸焦磷酸磷酸二酯酶 (ENPP1) 已被证明可以负向调节胰岛素受体，并在各种细胞类型中过度表达时诱导细胞胰岛素抵抗。当 ENPP1 在转基因模型的多个组织中过度表达时，也观察到全身胰岛素抵抗，这主要归因于骨骼肌和肝脏中诱导的组织胰岛素抵抗。调节葡萄糖和脂质代谢的另一个关键组织是脂肪组织（AT）。有趣的是，据报道，患有胰岛素抵抗的肥胖患者 AT ENPP1 表达增加。然而，ENPP1在AT中的具体作用尚未研究。为了更好地了解 AT ENPP1 对全身代谢的具体作用，我们创建了一个转基因小鼠模型（C57/Bl6 背景），在转基因构建体 (AdiposeENPP1-TG) 中使用 aP2 启动子，在脂肪细胞中靶向过度表达人 ENPP1。使用常规饲料或配对喂养方案和 60% 脂肪饮食，我们比较了 AdiposeENPP1-TG 和野生型 (WT) 兄弟姐妹的身体脂肪含量和分布以及脂肪、肌肉和肝脏组织中的胰岛素信号。我们还比较了腹膜内葡萄糖耐量试验（IPGTT）和胰岛素耐量试验（ITT）的反应。我们的结果显示，常规饮食喂养的脂肪 ENPP1-TG 小鼠没有变化。采用配对喂养方案进行高脂肪饮食后，AdiposeENPP1-TG 和 WT 小鼠的体重相似。然而，AdiposeENPP1-TG 小鼠发生脂肪肝与 AT 变化相关，其特征是脂肪细胞尺寸变小以及胰岛素受体 Tyr(1361) 和 Akt Ser(473) 磷酸化降低。 AT 功能和脂肪分布的这些变化与脂质和葡萄糖代谢的系统异常相关，包括 IPGTT 期间脂肪酸、甘油三酯、血浆葡萄糖和胰岛素的血浆浓度升高，以及 ITT 期间葡萄糖抑制的降低。因此，我们的结果表明，在高脂肪饮食的情况下，脂肪细胞中 ENPP1 过度表达会诱发脂肪肝、高脂血症和血糖异常，从而概括代谢综合征的关键表现。
Pan W, Ciociola E, Saraf M, Tumurbaatar B, Tuvdendorj D, Prasad S, Chandalia M, Abate N. Metabolic consequences of ENPP1 overexpression in adipose tissue. Am J Physiol Endocrinol Metab 301: E901-E911, 2011. First published August 2, 2011; doi: 10.1152/ajpendo.00087.2011.-Ectonucleotide pyrophosphate phosphodiesterase (ENPP1) has been shown to negatively modulate insulin receptor and to induce cellular insulin resistance when overexpressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is overexpressed in multiple tissues of transgenic models and attributed largely to tissue insulin resistance induced in skeletal muscle and liver. Another key tissue in regulating glucose and lipid metabolism is adipose tissue (AT). Interestingly, obese patients with insulin resistance have been reported to have increased AT ENPP1 expression. However, the specific effects of ENPP1 in AT have not been studied. To better understand the specific role of AT ENPP1 on systemic metabolism, we have created a transgenic mouse model (C57/Bl6 background) with targeted overexpression of human ENPP1 in adipocytes, using aP2 promoter in the transgene construct (AdiposeENPP1-TG). Using either regular chow or pair-feeding protocol with 60% fat diet, we compared body fat content and distribution and insulin signaling in adipose, muscle, and liver tissues of AdiposeENPP1- TG and wild-type (WT) siblings. We also compared response to intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT). Our results show no changes in Adipose ENPP1-TG mice fed a regular chow diet. After high-fat diet with pair-feeding protocol, AdiposeENPP1-TG and WT mice had similar weights. However, AdiposeENPP1-TG mice developed fatty liver in association with changes in AT characterized by smaller adipocyte size and decreased phosphorylation of insulin receptor Tyr(1361) and Akt Ser(473). These changes in AT function and fat distribution were associated with systemic abnormalities of lipid and glucose metabolism, including increased plasma concentrations of fatty acid, triglyceride, plasma glucose, and insulin during IPGTT and decreased glucose suppression during ITT. Thus, our results show that, in the presence of a high-fat diet, ENPP1 overexpression in adipocytes induces fatty liver, hyperlipidemia, and dysglycemia, thus recapitulating key manifestations of the metabolic syndrome.