Novel Role of ??-Adrenergic Receptors to Activate the mTOR-S6K1 Signaling Pathway

??-肾上腺素能受体激活 mTOR-S6K1 信号通路的新作用

• 批准号: 8055361
• 负责人: SHEILA COLLINS
• 金额: $ 23.64万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055361
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Receptor; Amino Acids; Angiogenic Factor; Area; Biological; Blood Vessels; Catecholamines; Cellular biology; Code; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Desire for food; Development; Epinephrine; Etiology; Fatty acid glycerol esters; Fractionation; Glucose; Glycerol; Growth; Growth Factor; Healthcare Systems; Hormones; Human; Immune response; Incidence; Insulin; Insulin Signaling Pathway; Intervention; Investigation; Laboratories; Lead; Lipolysis; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Muscle; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Norepinephrine; Nutrient; Obesity; Pathway interactions; Peptides; Phase; Phosphorylation; Phosphotransferases; Polyribosomes; Principal Investigator; Process; Production; Productivity; Protein Kinase; Proteins; Quality of life; Research Project Grants; Rodent; Role; Set protein; Signal Pathway; Signaling Molecule; Source; System; Testing; Time; Tissues; Transcript; Translations; adipokines; cell growth; fighting; human FRAP1 protein; insulin sensitivity; lipid biosynthesis; novel; programs; promoter; public health relevance; response

DESCRIPTION (provided by applicant): Activation of ¿-adrenergic receptors (¿ARs) in adipocytes by E/NE increases cAMP levels and cAMP- dependent protein kinase (PKA) activity. PKA phosphorylates several key targets that promote lipolysis to release free fatty acids and glycerol. Opposing this catabolic response is insulin, which stimulates lipogenesis and fuel conservation in adipocytes. Insulin is also an important growth promoter though its ability to activate the mTOR-S6K1 pathway. mTOR is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues such as growth factors, and nutrients such as glucose and amino acids. Consistent with their opposing functions in fat, the insulin and catecholamine systems also antagonize eachother's signaling pathways at several levels, thus providing dynamic and sensitive control of energy needs. In addition to the traditional role of ¿ARs in the stimulation of lipolysis and suppression of insulin- action, our new studies unexpectedly show that ¿ARs activate the mTOR-S6K1 pathway in a cAMP and PKA dependent manner. This activity can be observed in human and rodent fat cells, white and brown adipocytes. This pathway is principally involved in the regulated translation of specific sets of mRNAs. The fat cell is increasingly recognized as an important source of peptide adipokines, angiogenic factors, and perhaps even other peptide neurotransmitters, but there is limited understanding of how these factors are synthesized, regulated or secreted. The studies proposed here in this R21 Pilot and Feasiblility project will test the following two specific hypotheses: (1) The role of ¿AR and cAMP-stimulated S6K1 activity in adipocytes is to selectively stimulate the translation of a set of mRNAs that are distinct from those regulated by insulin, and we propose to identify these transcripts. The approach taken involves polysome fractionation followed by microarray profiling of differentially redistributed transcripts. (2) The role of ¿AR and cAMP-stimulated S6K1 activity in adipocytes is to desensitize the insulin-signaling pathway, and this is achieved through Ser phosphorylation of IRS-1 by S6K1. Given the integrative role of adipose tissue in the etiology of metabolic syndrome, this exploratory research project provides both an opportunity to expand the terrain from which new targets for intervention in metabolic disease might be identified, as well as promote our basic understanding of the cell biology of the adipocyte. PUBLIC HEALTH RELEVANCE: The continuing escalation in the incidence of Type II diabetes in the US (and around the world) is placing an enormous burden on the health care system, on worker productivity and on quality of life for those afflicted. We know a great deal of information about the steps in the cascade of intracellular actions of insulin and how they tend to be perturbed in the early phases of the development of Type II diabetes. We know that the ability of fat cells to store energy and to regulate its release is an important component of proper nutrient partitioning in the body. However the fat cell is not only a bank in which excess metabolic energy is stored as currency for use during times of caloric deficit, but it is also an important source of protein hormones. These include hormones to control appetite, proper insulin action in other tissue such as muscle, and fat is even a source of factors to regulate blood vessel growth and immune responses. There is also increasing appreciation that fat cells can also be net consumers of energy and thus have the potential to even fight obesity. However, compared to what we know about fat storage and release, we know comparatively very little about the control of fat cell-derived hormones and signaling molecules, which are themselves controlled by circulating hormones such as insulin and adrenaline. The purpose of this proposal is to test new ideas that developed from unexpected new findings in our laboratory, in which we propose to demonstrate that there are unique processes in fat cells that control non-overlapping sets of protein production, and we postulate that some of these differentially regulated proteins will code for these fat cell-derived hormones.

描述（由申请方提供）：E/NE激活脂肪细胞中的<$-肾上腺素能受体（<$AR）可增加cAMP水平和cAMP依赖性蛋白激酶（PKA）活性。PKA磷酸化促进脂解的几个关键靶标以释放游离脂肪酸和甘油。对抗这种分解代谢反应的是胰岛素，它刺激脂肪细胞中的脂肪生成和燃料保存。胰岛素也是一种重要的生长促进剂，尽管它能够激活mTOR-S6 K1通路。mTOR是一种保守的Ser/Thr激酶，其响应于环境线索（例如生长因子）和营养物（例如葡萄糖和氨基酸）来调节细胞生长和代谢。与它们在脂肪中的相反功能一致，胰岛素和儿茶酚胺系统也在几个水平上拮抗彼此的信号传导途径，从而提供对能量需求的动态和灵敏的控制。除了AR在刺激脂解和抑制胰岛素作用中的传统作用外，我们的新研究意外地显示AR以cAMP和PKA依赖性方式激活mTOR-S6 K1通路。在人和啮齿动物脂肪细胞、白色和棕色脂肪细胞中可观察到该活性。该途径主要参与特定mRNA组的调节翻译。脂肪细胞越来越多地被认为是肽脂肪因子、血管生成因子甚至其他肽神经递质的重要来源，但对这些因子如何合成、调节或分泌的了解有限。在R21 Pilot和Functionality项目中提出的研究将测试以下两个特定假设：（1）AR和cAMP刺激的S6 K1活性在脂肪细胞中的作用是选择性地刺激一组mRNA的翻译，这些mRNA与胰岛素调节的mRNA不同，我们建议鉴定这些转录本。所采取的方法涉及多核糖体分馏，然后通过微阵列分析差异重新分布的转录本。(2)的作用在脂肪细胞中，AR和cAMP刺激的S6 K1活性是为了使胰岛素信号通路脱敏，这是通过S6 K1对IRS-1的Ser磷酸化来实现的。考虑到脂肪组织在代谢综合征病因学中的综合作用，这项探索性研究项目提供了一个机会，可以扩大代谢疾病干预新靶点的范围，并促进我们对脂肪细胞细胞生物学的基本理解。 公共卫生相关性：美国（以及世界各地）II型糖尿病发病率的持续上升给医疗保健系统、工人生产力和患者的生活质量带来了巨大负担。我们知道大量关于胰岛素细胞内作用级联的步骤以及它们在II型糖尿病发展的早期阶段如何受到干扰的信息。我们知道，脂肪细胞储存能量和调节能量释放的能力是体内适当营养分配的重要组成部分。然而，脂肪细胞不仅是一个银行，其中多余的代谢能量储存作为货币使用时，热量不足，但它也是一个重要的来源蛋白质激素。这些包括控制食欲的激素，其他组织（如肌肉）中适当的胰岛素作用，脂肪甚至是调节血管生长和免疫反应的因素来源。人们也越来越认识到，脂肪细胞也可以是能量的净消费者，因此有可能甚至对抗肥胖。然而，与我们对脂肪储存和释放的了解相比，我们对脂肪细胞衍生的激素和信号分子的控制知之甚少，这些激素和信号分子本身由胰岛素和肾上腺素等循环激素控制。这项提案的目的是测试我们实验室中意外的新发现所产生的新想法，我们建议证明脂肪细胞中存在控制非重叠蛋白质生产的独特过程，并且我们假设这些差异调节的蛋白质中的一些将编码这些脂肪细胞衍生的激素。