Altered endocannabinoid signalling after a high-fat diet in Apoe-/- mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance
Altered endocannabinoid signalling after a high-fat diet in Apoe-/- mice: relevance to adipose tissue inflammation, hepatic steatosis and insulin resistance
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DOI：
10.1007/s00125-011-2274-6
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发表时间：
2011-11-01
期刊：
影响因子：
8.2
通讯作者：
Di Marzo, V.
中科院分区：
文献类型：
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作者：
Bartelt, A.;Orlando, P.;Di Marzo, V.
载脂蛋白E（ApoE）缺乏与白色脂肪组织（WAT）中脂肪蓄积减少以及肝脏三酰甘油含量升高有关。肝脏以及附睾白色脂肪组织相较于皮下白色脂肪组织中内源性大麻素和1型大麻素受体（CB1）水平升高与脂肪肝、内脏脂肪组织、炎症标志物和胰岛素抵抗有关。我们在载脂蛋白E基因敲除（Apoe -/-）小鼠和野生型（WT）小鼠中研究了高脂饮食（HFD）对以下方面的影响：（1）皮下和附睾白色脂肪组织蓄积、肝脏三酰甘油、磷脂酯化脂肪酸、白色脂肪组织和肝脏中的炎症标志物以及胰岛素抵抗；（2）内源性大麻素水平，以及肝脏和白色脂肪组织中CB1受体和内源性大麻素代谢酶的基因表达水平。
经过16周的高脂饮食后，与野生型小鼠相比，载脂蛋白E基因敲除小鼠体重更低，白色脂肪组织蓄积更少，空腹瘦素、葡萄糖和胰岛素水平更低，而肝脏脂肪变性更严重。高脂饮食后，野生型小鼠的葡萄糖清除和胰岛素介导的葡萄糖处置比载脂蛋白E基因敲除小鼠更慢，载脂蛋白E基因敲除小鼠肝脏中编码炎症标志物（肿瘤坏死因子 -α[TNF -α]、单核细胞趋化蛋白 -1[MCP -1]、分化簇68[CD68]和含表皮生长因子样模块的粘蛋白样激素受体样1[EMR1]）的mRNA水平更高，但附睾白色脂肪组织中水平更低。在载脂蛋白E基因敲除小鼠中，高脂饮食诱导的肝脏或附睾白色脂肪组织内源性大麻素水平升高分别更高或更低，而高脂饮食诱导的皮下白色脂肪组织内源性大麻素和CB1受体水平下降明显不显著。内源性大麻素水平的变化反映了白色脂肪组织内源性大麻素分解代谢酶的变化，或肝脏中磷脂前体的可利用性。
高脂饮食后肝脏和脂肪组织的内源性大麻素水平在载脂蛋白E缺失时发生改变，并与炎症、胰岛素抵抗和肝脏脂肪变性（或无肝脏脂肪变性）密切相关。
Apolipoprotein E (ApoE) deficiency is associated with reduced fat accumulation in white adipose tissue (WAT) and high liver triacylglycerol content. Elevated levels of endocannabinoids and cannabinoid receptor type 1 (CB1) receptors in the liver and in epididymal vs subcutaneous WAT are associated with fatty liver, visceral adipose tissue, inflammatory markers and insulin resistance.We investigated, in Apoe (-/-) and wild-type (WT) mice, the effect of a high-fat diet (HFD) on: (1) subcutaneous and epididymal WAT accumulation, liver triacylglycerols, phospholipid-esterified fatty acids, inflammatory markers in WAT and liver, and insulin resistance; and (2) endocannabinoid levels, and the gene expression levels of the Cb (1) receptor and endocannabinoid metabolic enzymes in liver and WAT.After a 16 week HFD, Apoe (-/-) mice exhibited lower body weight, WAT accumulation and fasting leptin, glucose and insulin levels, and higher hepatic steatosis, than WT mice. Glucose clearance and insulin-mediated glucose disposal following the HFD were slower in WT than Apoe (-/-) mice, which exhibited higher levels of mRNA encoding inflammatory markers (tumour necrosis factor-alpha [TNF-alpha], monocyte chemoattractant protein-1 [MCP-1], cluster of differentiation 68 [CD68] and EGF-like module-containing mucin-like hormone receptor-like 1 [EMR1]) in the liver, but lower levels in epididymal WAT. HFD-induced elevation of endocannabinoid levels in the liver or epididymal WAT was higher or lower, respectively, in Apoe (-/-) mice, whereas HFD-induced decrease of subcutaneous WAT endocannabinoid and CB1 receptor levels was significantly less marked. Alterations in endocannabinoid levels reflected changes in endocannabinoid catabolic enzymes in WAT, or the availability of phospholipid precursors in the liver.Liver and adipose tissue endocannabinoid tone following an HFD is altered on Apoe deletion and strongly associated with inflammation, insulin resistance and hepatic steatosis, or lack thereof.