Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities
Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities
复制标题
DOI：
10.1074/jbc.m110970200
复制
发表时间：
2002-03-08
影响因子：
4.8
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
--
作者：
Razani, B;Combs, TP;Lisanti, MP
小窝细胞器和小窝蛋白-1在脂肪细胞和内皮细胞中表达最丰富。我们对缺乏小窝蛋白-1（Cav-1）的小鼠的初步报告表明，小窝的损失和内皮细胞功能的扰动。然而，最近，观察到的Cav-1缺陷的队列到老年显着降低体重，与野生型对照组相比。这些结果表明Cav-1缺失小鼠可能具有脂质代谢和/或脂肪细胞功能的问题。为了直接检验这一假设，我们将一组野生型和Cav-1缺失小鼠置于高脂肪饮食中。有趣的是，尽管是贪食的，但Cav-1缺失小鼠显示出对饮食诱导的肥胖的明显抗性。如所预测的，来自Cav-1无效小鼠的脂肪细胞缺乏小窝膜。早期，缺乏小窝蛋白-1选择性地仅影响女性乳腺脂肪垫，并导致皮下脂肪层几乎完全消融。还有全身脂肪组织病理学的迹象。随着年龄的增长，发生脂质蓄积的全身性代偿失调，导致脂肪垫显著变小，组织学上脂肪细胞直径减小，分化不良/细胞过多的白色脂肪实质。为了获得对这种表型的机制性见解，我们表明，虽然血清胰岛素，葡萄糖和胆固醇水平是完全正常的，Cav-1基因敲除小鼠有严重升高的甘油三酯和游离脂肪酸水平，特别是在餐后状态。然而，这种富含甘油三酯的乳糜微粒/极低密度脂蛋白的积聚不是由于脂蛋白脂肪酶活性受到干扰，而脂蛋白脂肪酶活性是孤立性高甘油三酯血症的主要罪魁祸首。在Cav-1缺失小鼠中观察到的瘦体表型和代谢缺陷与先前提出的小窝蛋白-1和小窝在脂肪细胞中的功能一致。我们的研究结果首次表明，明确的作用，在体内系统脂质稳态和地方小窝蛋白-1/小窝作为高血压和肥胖症的主要因素。
Caveolae organelles and caveolin-1 protein expression are most abundant in adipocytes and endothelial cells. Our initial report on mice lacking caveolin-1 (Cav-1) demonstrated a loss of caveolae and perturbations in endothelial cell function. More recently, however, observation of the Cav-1-deficient cohorts into old age revealed significantly lower body weights, as compared with wild-type controls. These results suggest that Cav-1 null mice may have problems with lipid metabolism and/or adipocyte functioning. To test this hypothesis directly, we placed a cohort of wild-type and Cav-1 null mice on a high fat diet. Interestingly, despite being hyperphagic, Cav-1 null mice show overt resistance to diet-induced obesity. As predicted, adipocytes from Cav-1 null null mice lack caveolae membranes. Early on, a lack of caveolin-1 selectively affects only the female mammary gland fat pad and results in a near complete ablation of the hypo-dermal fat layer. There are also indications of generalized adipose tissue pathology. With increasing age, a systemic decompensation in lipid accumulation occurs resulting in dramatically smaller fat pads, histologically reduced adipocyte cell diameter, and a poorly differentiated/hypercellular white adipose parenchyma. To gain mechanistic insights into this phenotype, we show that, although serum insulin, glucose, and cholesterol levels are entirely normal, Cav-1 null mice have severely elevated triglyceride and free fatty acid levels, especially in the postprandial state. However, this build-up of triglyceride-rich chylomicrons/very low density lipoproteins is not due to perturbed lipoprotein lipase activity, a major culprit of isolated hypertriglyceridemia. The lean body phenotype and metabolic defects observed in Cav-1 null mice are consistent with the previously proposed functions of caveolin-1 and caveolae in adipocytes. Our results show for the first time a clear role for caveolins in systemic lipid homeostasis in vivo and place caveolin-1/ caveolae as major factors in hyperlipidemias and obesity.