Monoglyceride Lipase Deficiency in Mice Impairs Lipolysis and Attenuates Diet-induced Insulin Resistance
Monoglyceride Lipase Deficiency in Mice Impairs Lipolysis and Attenuates Diet-induced Insulin Resistance
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DOI：
10.1074/jbc.m110.215434
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Zimmermann, Robert
中科院分区：
文献类型：
--
作者：
Taschler, Ulrike;Radner, Franz P. W.;Zimmermann, Robert
单甘油酯脂肪酶（MGL）通过至少两种机制影响能量代谢。首先，它将单酰基甘油（MG）水解成脂肪酸和甘油。这些产物可用于能源生产或合成反应。其次，MGL降解2-花生四烯醇甘油（2-AG），这是大麻素受体（CBR）最丰富的内源性配体。CBR的激活通过中枢外氧刺激、促进脂质储存和减少能量消耗来影响能量稳态。为了表征MGL在体内的代谢作用，我们建立了一个MGL缺陷小鼠模型（MGL-ko）。这些小鼠表现出MG水解酶活性降低，同时脂肪组织、大脑和肝脏中MG水平升高。在脂肪组织中，MGL活性的缺乏部分由激素敏感的脂肪酶补偿。尽管如此，禁食的MGL-ko小鼠表现出血浆甘油和甘油三酯水平降低，以及肝脏甘油三酯水平降低，表明脂肪分解受损。尽管2-AG水平明显升高，但MGL-ko小鼠表现出正常的食物摄入、脂肪量和能量消耗。然而，缺乏MGL的小鼠对CBR激动剂CP 55,940表现出药理学耐受性，这表明升高的2-AG水平可以通过CBR脱敏在功能上拮抗。然而，有趣的是，与野生型对照组相比，接受高脂肪饮食的MGL-ko小鼠表现出显著改善的葡萄糖耐量和胰岛素敏感性，尽管体重增加相同。总之，我们的观察结果表明，MGL缺乏损害脂肪分解和减轻饮食引起的胰岛素抵抗。2-AG的缺陷降解不会引起大麻素对摄食行为、脂质储存和能量消耗的类似影响，这可能是由CBR的脱敏性来解释的。
Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.