Adipose Tissue Angiogenesis and Metabolic Disease

脂肪组织血管生成和代谢疾病

• 批准号: 9269567
• 负责人: Silvia Corvera
• 金额: $ 46.51万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269567
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Agonist; Animal Model; Bioinformatics; Blood capillaries; Calories; Cells; Characteristics; Clinical Research; Consumption; Cues; Diagnostic; Disease; Energy Metabolism; Environmental Risk Factor; Euglycemic Clamping; Foundations; Gene Expression Profiling; Genetic; Glucose; Glucose Clamp; Health; Heart Diseases; Human; Human Cloning; Human body; Implant; In Vitro; Investigation; Laboratories; Leg; Link; Lipids; Liver; Mass Spectrum Analysis; Messenger RNA; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Muscle; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Peptides; Peripheral; Phenotype; Physiology; Population; Proliferating; Property; Proprotein Convertases; Proteome; Proteomics; RNA; Role; Signs and Symptoms; Skin; Stimulus; Temperature; Therapeutic; Therapeutic Uses; Thermogenesis; Tissues; Work; adipocyte differentiation; angiogenesis; arm; base; capillary; deep sequencing; defined contribution; enhancing factor; experimental study; glucose disposal; glucose metabolism; glucose tolerance; high risk; human tissue; implantation; improved; in vivo; indexing; insulin sensitivity; metabolic phenotype; non-alcoholic; non-alcoholic fatty liver; novel; progenitor; public health relevance; response; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): Metabolic diseases, including type 2 diabetes and non-alcoholic fatty liver disease, arise from disordered energy utilization and storage, and are therefore directly linked to the physiology of adipose tissue. Many adult humans possess metabolically active "beige" adipose tissue, and its mass shows an inverse correlation with adiposity and a direct correlation with metabolic health. How this tissue arises, responds to environmental cues, and its potential for diagnostic and therapeutic use are exciting questions currently under investigation. However, adequate models to study this tissue from humans are lacking. This proposal is based on an exciting recent finding from our laboratory that enables the isolation and expansion of human primary pre-adipocytes that give rise to white and "beige" adipocytes. We discovered that human "beige" pre-adipocytes are localized within the adipose tissue vasculature, and proliferate only under conditions that promote capillary network expansion in vitro. We now seek to leverage these findings to understand the cell and molecular basis for the formation of these cells, and the mechanisms underlying their beneficial metabolic effects. Specific Aim 1: Using new deep sequencing and bioinformatics approaches that enable cell annotation using very low RNA input we will determine whether white and "beige" adipocytes emerge from the same or distinct pre-adipocyte progenitors. Specific Aim 2: Our preliminary studies indicate that implantation of human "beige" adipocytes into NOD-scid IL2rγnull (NSG) mice improves glucose disposal, suggesting that cells per-se can confer a metabolic benefit. We will determine whether implanted human "beige" adipocytes improve systemic glucose metabolism by acting as an energy sink for glucose and lipid utilization, or by secreting factors that enhance glucose tolerance and insulin sensitivity in other tissues. Specific Aim 3: Our new findings from gene expression analysis of human "beige" adipocytes has revealed induction of mRNAs for potent neuroendocrine factors, including the pro-protein convertase PCSK1 which is genetically associated with obesity in numerous human populations. Thus, the beneficial effect of human "beige" adipocytes may be due to a neuroendocrine function. Mass spectroscopy has confirmed the secretion of fragments of PCSK1, and identified novel secreted peptides. Proteomic analysis proposed here will further define the secreted proteome from these cells, and provide information necessary for analyzing its impact on systemic glucose tolerance. The work proposed will answer pivotal questions regarding the origin, characteristics and functional properties of human "beige" adipocytes and their secreted products, and provide the foundation for clinical studies leveraging these findings for diagnostic and therapeutic applications in human metabolic disease.

 描述（由申请人提供）：代谢疾病，包括2型糖尿病和非酒精性脂肪肝，是由能量利用和储存紊乱引起的，因此与脂肪组织的生理学直接相关许多成年人具有代谢活跃的“米色”。 “脂肪组织及其质量与肥胖呈负相关，与代谢健康呈正相关。这种组织如何产生、对环境信号做出反应以及其诊断和治疗用途的潜力是目前令人兴奋的问题然而，尚缺乏足够的模型来研究人类的这种组织，该提议基于我们实验室最近的一项令人兴奋的发现，该发现能够分离和扩增产生白色和“米色”脂肪细胞的人类原代前脂肪细胞。我们发现人类“米色”前脂肪细胞位于脂肪组织脉管系统内，并且仅在体外促进毛细血管网络扩张的条件下增殖。我们现在寻求利用这些发现来了解形成的细胞和分子基础。具体目标 1：使用新的深度测序和生物信息学方法，使用非常低的 RNA 输入进行细胞注释，我们将确定白色和“米色”脂肪细胞是否来自相同或不同的预脂肪细胞。具体目标 2：我们的初步研究表明，将人类“米色”脂肪细胞植入 NOD-scid IL2rγnull (NSG) 小鼠中可以改善葡萄糖处理，这表明细胞我们将确定植入的人类“米色”脂肪细胞是否通过充当葡萄糖和脂质利用的能量库，或通过分泌增强其他组织的葡萄糖耐量和胰岛素敏感性的因子来改善全身葡萄糖代谢。具体的 目标 3：我们对人类“米色”脂肪细胞的基因表达分析的新发现揭示了有效神经内分泌因子的 mRNA 诱导，包括前蛋白转化酶 PCSK1，它与许多人群的肥胖遗传相关。人类“米色”脂肪细胞可能是由于具有神经内分泌功能而分泌的PCSK1片段，并且本文提出的新的分泌肽分析将进一步明确。这些细胞分泌的蛋白质组，并提供分析其对全身葡萄糖耐量的影响所需的信息，该工作将回答有关人类“米色”脂肪细胞及其分泌产物的起源、特征和功能特性的关键问题，并提供基础。用于利用这些发现在人类代谢疾病的诊断和治疗应用中的临床研究。