Regulation of Lipid Storage by mTORC1

mTORC1 对脂质储存的调节

• 批准号: 9207756
• 负责人: Dave Bridges
• 金额: $ 34.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207756
• 关键词: ADD-1 protein; Ablation; Adipocytes; Adipose tissue; Adult; Affect; American; Animals; Binding; Cause of Death; Characteristics; Chronic; Comorbidity; Development; Diet; Epidemic; Fatty Liver; Fatty acid glycerol esters; Feedback; Functional disorder; Genes; Genetic Transcription; Homeostasis; Individual; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Link; Lipids; Liver; Liver diseases; Maintenance; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; MicroRNAs; Modeling; Molecular; Mus; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated liver disease; PPAR gamma; Pathway interactions; Phosphotransferases; Physiological; Play; Process; Public Health; Rattus; Refractory; Regulation; Resistance; Rodent; Role; Route; Signal Transduction; Societies; TSC1 gene; Testing; Therapeutic Intervention; Thinness; Time; Tissues; Weight Gain; detection of nutrient; experimental study; feeding; genome editing; in vivo; innovation; insight; insulin sensitivity; lipid biosynthesis; lipid metabolism; mRNA Stability; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; obesity management; promoter; public health relevance; transcription factor

 DESCRIPTION (provided by applicant): Obesity is a public health epidemic wordwide and affects nearly a third of adult Americans. Several devastating co-morbidities are associated with obesity, including insulin resistance/type II diabetes and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease. Paradoxically, in obese states, lipid storage is not suppressed, in spite of resistance to insulin action. This finding that has important consequences for the management of obesity and its complications. An emerging molecular mechanism linking obesity to excessive lipid storage is the mTORC1/SREBP1c pathway, which our group and others have identified as both activated with obesity, and as a key regulator of lipogenesis and new adipocyte formation. This study will test the hypothesis that mTORC1 activation in the obese state elevates lipid levels, due to activation of both adipogenesis and lipogenesis. To accomplish this, we have developed several new innovative models to test specific aspects of this hypothesis. First, we have generated adipose-specificTsc1 knockout mice as a model of chronic adipose mTORC1 activation. The chronic elevations in mTORC1 signaling in these mice are associated with elevated fat mass and increased hepatic steatosis, likely due to enhanced de novo lipogenesis in adipose tissue. We will determine the molecular changes resulting from chronic mTORC1 elevation, and identify the molecular mechanisms underlying these mTORC1-dependent increases in lipid storage. Elevated adiposity may is caused by increased adipogenesis, so we will determine the molecular mechanisms by which mTORC1 positively regulates adipogenesis. We will specifically evaluate the hypothesis that mTORC1 regulates PPARγ mRNA stability via a miRNA-dependent mechanism. To test the role of mTORC1 in the liver, we will study both activation and inhibition this kinase via ablation of the essential mTORC1 component Rptor, and Tsc1 respectively in adult mouse livers. This approach will allow us to evaluate whether mTORC1 is necessary and sufficient for the development and maintenance of hepatic steatosis in adult liver tissues for the first time. This is an important gp in our knowledge, since in obesity-associated liver disease, mTORC1 is not activated during development, but co-incident with elevations in adiposity. We will explore the physiological significance of a positive feedback loop in SREBP1c using genome-edited rats. This key mTORC1 target plays an important role in de novo lipogenesis and the amplification of SREBP1c action by a transcriptional feed-forward circuit has been proposed to be an important component of both diet-induced hepatic steatosis and obesity. By deleting only the relevant SRE at the endogenous Srebf1 locus, we can test the importance of this circuit in a controlled and direct manner. Importantly, these rats will also allow us to separate the direct activation of SREBP1c by mTORC1 and other signals, from the confounding effects of positive feedback. Together these studies will answer fundamental mechanistic questions regarding how mTORC1 and SREBP1c regulate adipogenesis and lipogenesis, providing insights into potential routes of therapeutic intervention for obesity and liver disease.

 描述(申请人提供)：肥胖是一种全球公共卫生流行病，影响着近三分之一的美国成年人。几种毁灭性的并发症与肥胖有关，包括胰岛素抵抗/II型糖尿病和非酒精性脂肪性肝炎/非酒精性脂肪肝。矛盾的是，在肥胖状态下，脂肪储存并没有受到抑制，尽管对胰岛素的作用有抵抗。这一fi结果对肥胖及其并发症的管理具有重要影响。一个新出现的将肥胖与过度脂肪储存联系在一起的分子机制是mTORC1/SREBP1c途径，我们的团队和其他人发现它既被肥胖所激活，又是脂肪生成和新的脂肪细胞形成的关键调节因子。这项研究将检验这一假设，即肥胖状态下mTORC1的激活会提高血脂水平，这是因为脂肪生成和脂肪生成都被激活了。为了实现这一点，我们开发了几个新的创新模型来测试这一假说的特殊fic方面。首先，我们建立了脂肪特异性mTORC1cTsc1基因敲除小鼠，作为慢性脂肪fi激活的模型。这些小鼠中mTORC1信号的慢性升高与脂肪质量增加和肝脏脂肪变性增加有关，这可能是由于脂肪组织中新生脂肪生成的增强。我们将确定慢性mTORC1升高引起的分子变化，并确定这些mTORC1依赖的脂质储存增加背后的分子机制。肥胖增加可能是由脂肪生成增加引起的，因此我们将确定mTORC1积极调节脂肪生成的分子机制。我们将具体评估mTORC1miRNA依赖机制调节PPARmiRNA稳定性的假说。为了测试mTORC1在肝脏中的作用，我们将通过分别在成年小鼠肝脏中消融基本的mTORC1组分Rptor和TSC1来研究激活和抑制该激酶。这一方法将使我们能够第一次评估mTORc1对于成人肝组织中肝脂肪变性的发生和维持是否必要和充分。据我们所知，这是一个重要的GP，因为在肥胖相关的肝病中，mTORC1不是在发育过程中被激活，而是与肥胖症的升高同时发生。我们将使用基因组编辑的大鼠来探索SREBP1c中正反馈环的生理学意义。这个关键的mTORC1靶基因在新生脂肪形成中起着重要的作用，转录前馈电路对SREBP1c作用的放大被认为是饮食诱导的肝脏脂肪变性和肥胖的重要组成部分。通过只删除内源性Srebf1基因座上的相关SRE，我们可以控制和直接地测试该电路的重要性。重要的是，这些大鼠还将使我们能够将mTORC1和其他信号对SREBP1c的直接激活与正反馈的混淆效应分开。这些研究将共同回答有关mTORC1和SREBP1c如何调控脂肪生成和脂肪生成的基本机制问题，为肥胖和肝脏疾病的潜在治疗干预提供见解。