Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease.
Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease.
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DOI：
10.1016/j.molmet.2016.04.001
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发表时间：
2016-06
影响因子：
8.1
通讯作者：
Guertin DA
中科院分区：
文献类型：
--
作者：
Lee PL;Tang Y;Li H;Guertin DA
正常的脂肪组织生长和功能对维持代谢稳态至关重要，其过量（如肥胖）或缺乏（如脂肪营养不良）与严重的代谢疾病有关。本研究的目的是了解维持健康脂肪组织生长和功能的机制。脂肪组织感知并响应生长因子和养分有效性的系统性变化；在细胞中，mTORC1调节对生长因子和营养物质的代谢。因此，mTORC1被认为是脂肪细胞代谢的关键细胞内调节因子。在这里，我们研究了mTORC1在成熟脂肪细胞中的作用，通过生成和表征使用脂联素- cre驱动程序来删除Raptor的floxed等位基因的小鼠，Raptor编码mTORC1的一个重要调节亚基。RaptorAdipoq-cre小鼠在出生的最初几周具有正常的白色脂肪组织（WAT）质量，但此后很快发展为与肝肥大、肝脂肪变性和胰岛素不耐受相关的脂肪营养不良。RaptorAdipoq-cre小鼠在食用高脂肪饮食（HFD）时也不会变得肥胖。对肥胖的抵抗似乎不是由于能量消耗的增加，而是由于脂肪组织扩张失败，导致严重的肝肿大，与贪食和饮食脂肪吸收缺陷有关。在WAT中删除Raptor也会降低C/EBPα的表达及其下游目标脂联素的表达，这为mTORC1在WAT中的功能提供了一种可能的机制。成熟脂肪细胞中的mTORC1活性对于维持正常的脂肪组织生长至关重要，其在成熟脂肪细胞中的选择性丧失导致进行性脂肪营养不良疾病和全身性代谢疾病，这些疾病与人类先天性全身性脂肪营养不良有许多共同的特征。描述了一种新的Raptor （mTORC1）在脂肪组织中的损失模型。年轻肥胖的猛禽KO小鼠具有正常的WAT质量。Fat Raptor KO小鼠逐渐发展为脂肪营养不良和代谢疾病。Fat Raptor KO小鼠抵抗肥胖，但发展为严重的肝肿大。
Normal adipose tissue growth and function is critical to maintaining metabolic homeostasis and its excess (e.g. obesity) or absence (e.g. lipodystrophy) is associated with severe metabolic disease. The goal of this study was to understand the mechanisms maintaining healthy adipose tissue growth and function. Adipose tissue senses and responds to systemic changes in growth factor and nutrient availability; in cells mTORC1 regulates metabolism in response to growth factors and nutrients. Thus, mTORC1 is poised to be a critical intracellular regulator of adipocyte metabolism. Here, we investigate the role of mTORC1 in mature adipocytes by generating and characterizing mice in which the Adiponectin-Cre driver is used to delete floxed alleles of Raptor, which encodes an essential regulatory subunit of mTORC1. RaptorAdipoq-cre mice have normal white adipose tissue (WAT) mass for the first few weeks of life, but soon thereafter develop lipodystrophy associated with hepatomegaly, hepatic steatosis, and insulin intolerance. RaptorAdipoq-cre mice are also resistant to becoming obese when consuming a high fat diet (HFD). Resistance to obesity does not appear to be due to increased energy expenditure, but rather from failed adipose tissue expansion resulting in severe hepatomegaly associated with hyperphagia and defective dietary lipid absorption. Deleting Raptor in WAT also decreases C/EBPα expression and the expression of its downstream target adiponectin, providing one possible mechanism of mTORC1 function in WAT. mTORC1 activity in mature adipocytes is essential for maintaining normal adipose tissue growth and its selective loss in mature adipocytes leads to a progressive lipodystrophy disorder and systemic metabolic disease that shares many of the hallmarks of human congenital generalized lipodystrophy. A new model of Raptor (mTORC1) loss in adipose tissue is described. Young fat Raptor KO mice have normal WAT mass. Fat Raptor KO mice progressively develop lipodystrophy and metabolic disease. Fat Raptor KO mice resist obesity but develop severe hepatomegaly.