Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase
Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase
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DOI：
10.1152/ajpregu.1997.273.2.r683
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发表时间：
1997-08-01
影响因子：
2.8
通讯作者：
Eckel, RH
中科院分区：
文献类型：
--
作者：
Jensen, DR;Schlaepfer, IR;Eckel, RH
使用肌肉肌酸激酶启动子和增强子产生在骨骼肌中过表达人脂蛋白脂肪酶（LPL）的转基因（Tg）FVB/N小鼠。据推测，通过在肌肉中过表达LPL，高脂肪喂养诱导的肥胖症将通过将脂蛋白衍生的甘油三酯脂肪酸从脂肪组织中的储存转移到肌肉中的氧化而被预防。在高脂肪（HF）喂养前6周龄和HF（46.1%脂肪）或高碳水化合物（HC）喂养（11.5%脂肪）13周后19周龄对小鼠进行检查。在6周时，杂合子Tg小鼠的LPL在白色肌肉中增加11倍，在红色肌肉中增加2.5倍，但在心肌或脾、脑、肺、肾或脂肪组织中没有增加。Tg小鼠的血浆甘油三酯（mg/dl）较低（87 +/- 7 vs. 117 +/- 7，P < 0.0001），葡萄糖升高（201 +/- 9 vs. 167 +/- 8 mg/dl，P = 0.029）。Tg和非转基因（nTg）小鼠之间的体重无差异;然而，雄性Tg小鼠在6周时的胴体脂质含量（%体重）显著降低（7.5 +/- 1.0 vs. 9.0 +/-1.0%，P = 0.035）。雌性Tg小鼠在6周时的身体组成没有差异。总体而言，与nTg小鼠相比，当Tg小鼠喂食HC或HF饮食13周时，血浆甘油三酯（P < 0.001）和游离脂肪酸（P < 0.001）降低，而血浆葡萄糖（P = 0.01）和胰岛素（P = 0.05）升高。HF喂养使雄性（10.3 +/- 1.1 vs. 21.4 +/-2.6%，HC vs. HF，P < 0.001）和雌性nTg小鼠（6.7 +/- 0.9 vs. 12.9 +/-1.8%，P = 0.01）的胴体脂质含量增加两倍。然而，骨骼肌中LPL的靶向过表达阻止了Tg雄性小鼠（10.2 +/- 0.7 vs. 13.5 +/-2.2%，HC vs. HF，P = NS）和雌性Tg小鼠（6.8 +/- 0.6 vs. 10.1 +/-1.4%，P = NS）中HF饮食诱导的脂质蓄积。通过基因或药物递送增加肌肉中LPL活性的潜力可能被证明是预防和/或治疗人类肥胖的有效工具。
Transgenic (Tg) FVB/N mice were produced that overexpress human lipoprotein lipase (LPL) in skeletal muscle using the muscle creatine kinase promoter and enhancers. It was hypothesized that, by overexpressing LPL in muscle, high fat feeding-induced obesity would be prevented by diverting lipoprotein-derived triglyceride fatty acids away from storage in adipose tissue to oxidation in muscle. Mice were examined both at 6 wk of age before high fat (HF) feeding and at 19 wk of age after 13 wk of HF (46.1% fat) or high carbohydrate (HC) feeding (11.5% fat). At 6 wk in heterozygous Tg mice, LPL was increased 11-fold in white muscle and 2.5-fold in red muscle, but not in cardiac muscle or spleen, brain, lung, kidney, or adipose tissue. Plasma triglycerides (mg/dl) were lower in Tg mice (87 +/- 7 vs. 117 +/- 7, P < 0.0001), and glucose increased (201 +/- 9 vs. 167 +/- 8 mg/dl, P = 0.029). There were no differences in body weight between Tg and nontransgenic (nTg) mice; however, carcass lipid content (%body wt) was significantly decreased in male Tg mice at 6 wk (7.5 +/- 1.0 vs. 9.0 +/- 1.0%, P = 0.035). Body composition was not different in female Tg mice at 6 wk. Overall, when Tg mice were fed either a HC or HF diet for 13 wk, plasma triglycerides (P < 0.001) and free fatty acids (P < 0.001) were decreased, whereas plasma glucose (P = 0.01) and insulin (P = 0.05) were increased compared with nTg mice. HF feeding increased carcass lipid content twofold in both male (10.3 +/- 1.1 vs. 21.4 +/- 2.6%, HC vs. HF, P < 0.001) and female nTg mice (6.7 +/- 0.9 vs. 12.9 +/- 1.8%, P = 0.01). However, the targeted overexpression of LPL in skeletal muscle prevented HF diet-induced lipid accumulation in both Tg male (10.2 +/- 0.7 vs. 13.5 +/- 2.2%, HC vs. HF, P = NS) and female Tg mice (6.8 +/- 0.6 vs. 10.1 +/- 1.4%, P = NS). The potential to increase LPL activity in muscle by gene or drug delivery may prove to be an effective tool in preventing and/or treating obesity in humans.