Perilipin 5 in the Regulation of Adipose Tissue Function

Perilipin 5 在脂肪组织功能调节中的作用

基本信息

批准号：
9920140
负责人：
PERRY E BICKEL
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920140
关键词：
Address Adipocytes Adipose tissue Adrenergic Agonists Adult Attention Biogenesis Brown Fat Calories Capsid Proteins Catecholamines Cell Differentiation process Cell Nucleus Cell Respiration Cells Crista ampullaris Cyclic AMP-Dependent Protein Kinases Data Diabetes Mellitus Disease Doxycycline Economic Burden Electron Microscopy Elements Energy Metabolism Gene Expression Genetic Models Genetic Transcription Goals Health Heterogeneity Homeostasis Hormonal Human Human body Knock-out Knowledge Lipase Lipids Maintenance Mediating Metabolic Mitochondria Modeling Molecular Molecular Profiling Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Obesity Obesity Epidemic Overnutrition Oxidative Phosphorylation Pathway interactions Pharmacology Phosphorylation Physiological Positioning Attribute Pre-Clinical Model Prevalence Proteomics Publications Regulation Reporting Research Respiration Role SIRT1 gene Signal Transduction Stimulus Stress Therapeutic Thermogenesis Thinness Tissues Toxic effect Wild Type Mouse adipocyte differentiation adult obesity cardiovascular risk factor gain of function glucose metabolism healthspan hormonal signals human male improved indexing knockout gene lipid metabolism loss of function mouse model novel novel therapeutic intervention novel therapeutics overexpression perilipin progenitor programs response subcutaneous transcriptome sequencing

项目摘要

The rising prevalence of obesity and type 2 diabetes threatens to limit human health span and to impose overwhelming economic burdens. New therapeutic approaches are urgently needed. Since the discovery within the last decade of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled respiration. Brown adipocytes are concentrated in discrete depots of brown adipose tissue; whereas, beige adipocytes develop from progenitors within white adipose tissue (WAT) in response to specific stimuli, including cold and β3-adrenergic receptor agonists. Recent research has revealed key elements of the transcriptional machinery that governs brown/beige cell differentiation, as well as numerous factors that activate brown/beige adipocytes. Importantly, relatively little is known about the intracellular factors that integrate hormonal and environmental signals with the nuclear transcriptional machinery that activates thermogenesis in adipocytes. This project investigates one such factor, Perilipin 5, which was originally discovered as a lipid droplet coat protein expressed in highly oxidative tissues, including brown adipose tissue. Perilipin 5 has been studied primarily as a regulator of lipase access and activity on the lipid droplet. Another function of Perilipin 5 has emerged from the discovery that, following its phosphorylation by protein kinase A, Perilipin 5 boosts gene expression related to oxidative metabolism and to the thermogenic program through physical interaction with SIRT1 and PGC-1α in the nucleus. The underlying hypothesis of this application is that increasing Perilipin 5 in thermogenic adipocytes will sensitize them to activation by stimuli such as cold exposure and β3-adrenergic receptor agonists and enable effective energy dissipation to address obesity and improve metabolic health. The overall goal of this project is to establish a preclinical model for increasing the capacity of brown/beige adipocytes to dissipate excess energy acquired through overnutrition. Specific Aim 1 will define the physiological role of Perilipin 5 in brown adipose tissue (BAT) thermogenesis and systemic glucose and lipid metabolism in adult mice by means of novel mouse models of inducible, BAT-specific overexpression and knockout of Perilipin 5. Specific Aim 2 will investigate the role of Perilipin 5 in maintaining mitochondrial integrity in BAT during cold stress and will explore the heterogeneity of BAT adipocytes defined by Perilipin expression. Specific Aim 3 will determine whether Perilipin 5 is sufficient to sensitize WAT to beiging in adult mice subjected to physiological (cold exposure) or pharmacological (β3-adrenergic receptor agonist) stimuli, and whether Perilipin 5 is necessary for WAT beiging triggered by these stimuli. Completion of these Aims will establish Perilipin 5 as a critical integrator of hormonal and transcriptional signaling in thermogenic adipocytes and may suggest novel therapeutic strategies to unleash the thermogenic potential of fat cells.

肥胖症和2型糖尿病的患病率上升有可能限制人类的健康范围，并施加压倒性的经济伯恩斯。迫切需要新的治疗方法。自从成年人类的功能性棕色和米色脂肪细胞的最后十年中发现以来，很多关注的重点是利用这些热脂肪细胞通过未偶联的呼吸进行热量来消除多余能量的能力。棕色脂肪细胞集中在棕色脂肪组织的离散沉积物中。而米色脂肪细胞是从白色脂肪组织（WAT）内的祖细胞发展而来的，这些脂肪细胞响应于特定的刺激，包括感冒和β3-肾上腺素受体激动剂。最近的研究揭示了控制棕色/米色细胞分化的转录机械的关键要素，以及激活棕色/米色脂肪细胞的许多因素。重要的是，对于将马al和环境信号与激活脂肪细胞中热发生的核转录机制相结合的细胞内因子相对较少。该项目研究了一个这样的因素，即Peripin 5，该因素最初是在高度氧化组织（包括棕色脂肪组织）中表达的脂质液滴外套蛋白。 Perilipin 5主要作为脂肪酶访问和活性在脂质液滴上的调节剂。 Perilipin 5的另一个功能是从发现蛋白激酶A磷酸化的发现中出现的，Perilipin 5促进了与氧化物代谢相关的基因表达以及通过与SIRT1和PGC-1α的物理相互作用而与核中的PGC-1α相互作用相关的基因表达。该应用的基本假设是，在热脂肪细胞中增加钙蛋白5会通过刺激（例如冷暴露和β3-肾上腺素能受体激动剂）感知它们，从而使它们受到激活，并促进有效的能量耗散以解决肥胖症并改善代谢健康。该项目的总体目标是建立一个临床前模型，以增加棕色/米色脂肪细胞的能力，以消除通过营养不良获得的多余能量。具体目标1将通过新型的诱导型，蝙蝠特异性过表达和止动物5的小鼠模型来定义成年小鼠中钙蛋白5在成年小鼠中的生物作用，以及全身性葡萄糖和脂质代谢。脂肪细胞由钙蛋白表达定义。具体的目标3将确定perilipin 5是否足以感知到受到身体（冷暴露）或药理学（β3-肾上腺素能受体激动剂）刺激的成年小鼠的水，以及对这些刺激触发的Perilipin 5是否是必要的。这些目的的完成将建立PLIPIN 5作为热脂肪细胞中的马和转录信号传导的关键积分器，并可能提出新型的热策略来释放脂肪细胞的热潜力。