Healthier White Adipose by Recruitment of Beige/Brite Adipocytes

通过招募米色/白色脂肪细胞来获得更健康的白色脂肪

基本信息

批准号：
9233103
负责人：
STEPHEN ROBERT FARMER
金额：
$ 36.42万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-16 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233103
关键词：
Acetylation Adipocytes Adipose tissue Adult Affect Alanine Animals Axilla Basal metabolic rate Binding Biological Assay Blood Circulation Body Weight Body Weight decreased Cardiovascular Diseases Catabolism Cells Cervical Collaborations Comorbidity Consumption Data Data Set Deacetylation Development Diet Dietary Fats Disease Dissociation Energy Metabolism Enhancers Expenditure FGF21 gene Fibrosis Gene Targeting Generations Genes Genetic Transcription Goals Healthcare Homeostasis Human Hypoxia Incidence Individual Insulin Resistance Investigation Knowledge Ligand Binding Ligands Lipids Mass Spectrum Analysis Measures Mediator of activation protein Metabolic Metabolism Microarray Analysis Mitochondria Molecular Mus Mutation Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Nuclear Nutrient Obese Mice Obesity Outcome Oxides PPAR gamma Phenotype Phenylalanine Phosphorylation Phosphorylation Inhibition Physiological Play Post-Translational Protein Processing Process Protein Dephosphorylation Proteins RNA Recruitment Activity Regulation Regulatory Element Rodent Role SIRT1 gene Serine Stimulus Supraclavicular Testing Therapeutic Thiazolidinediones Tissues Triglycerides United States angiogenesis base combat design energy balance flexibility gene repression innovation insulin sensitizing drugs novel novel therapeutics oxidation pandemic disease prevent promoter public health relevance response selective expression therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Obesity has reached pandemic proportions contributing to the dramatic increases in the incidence of type 2- diabetes and cardiovascular disease. The expansion of adipose tissue in obese individuals is a direct cause of these diseases due to an excessive accumulation of triglycerides (TGs) within white adipose (WAT) adipocytes. There are two major types of adipose, white that stores TGs and brown (BAT) that oxidizes them to produce heat. Until recently, it was thought that BAT only existed within the interscapular regions of newborns, but several recent investigations have identified BAT depots in the cervical, supraclavicular, axillary and paravertebral regions of adult humans. The contribution of BAT to resting metabolic rate and healthy body weight homeostasis in animals is now well established. In obese individuals, long-term weight loss can only be maintained if the "adipostat" is readjusted to a lower level. The mechanisms participating in this adipostat are not known in detail, but BAT appears to play an important role. BAT is a flexible tissue that can be recruited by various stimuli including cold exposure in rodents and humans. In fact, many earlier studies implicated the recruitment of brown adipocytes to WAT to explain changes in energy balance in response to different effectors. We have recently shown that the synthetic PPARγ ligand class of insulin sensitizers induces BAT functions in white adipocytes in mice and in culture. Establishment of this brite/beige phenotype by PPARγ involves a selective expression of BAT and hypoxia-responsive genes as well as repression of genes associated with insulin resistance. We have also discovered that this unique browning activity is regulated by a dephosphorylation of S273 as well as deacetylation of K268/K293 within the ligand-binding region of PPARγ. Based on these data, we hypothesize that the "browning" of WAT is regulated by post-translational modifications of PPARγ in response to changes in nutrient/metabolic status of the individual. We propose three aims to test this hypothesis. In Aim 1, we will define the phenotypes of the brown-like adipocytes recruited to WAT in response to posttranslational modification of PPARγ. In Aim 2, we will determine whether specific post-translationally modified PPARγ molecules bind to select regulatory elements in promoters/enhancers of target genes. In Aim 3, we will determine the effect of dephosphorylation on S273 or deacetylation of K268 and K293 of PPARγ on browning of white adipose tissue and energy expenditure in mice. Identifying the molecular mechanisms by which physiological effectors regulate the "browning" activity of PPARγ will significantly contribute to the development of therapeutics for obesity and it associated disorders.

描述（由适用提供）：肥胖症已达到大流行比例，导致2型糖尿病和心血管疾病事件的急剧增加。肥胖个体中脂肪组织的扩张是这些疾病的直接原因，因为白色脂肪（WAT）脂肪细胞中甘油三酸酯（TGS）的过量积累。有两种主要类型的脂肪，白色存储TGS和棕色（BAT），它们会产生热量。直到最近，人们认为BAT仅存在于新生儿的界面区域内，但是最近的一些调查已经确定了成年人类的颈椎，锁骨上，腋窝和副毛皮区域的蝙蝠沉积物。现在已经确定了蝙蝠对动物静息代谢率和健康体重稳态的贡献。在肥胖个体中，只有在将“脂肪仪”重新调整到较低水平时，才能保持长期体重减轻。参与此脂肪仪的机制尚不清楚，但BAT似乎起着重要作用。蝙蝠是一种柔性组织，可以通过各种刺激招募，包括啮齿动物和人类的冷暴露。实际上，许多早期的研究实施了募集棕色脂肪细胞以解释能量平衡的变化，以响应不同的影响。我们最近表明，胰岛素传感器的合成PPARγ配体类别在小鼠和培养中诱导蝙蝠的功能。 PPARγ建立这种Brite/米色表型涉及蝙蝠和缺氧反应性基因的选择性表达，以及与胰岛素抵抗相关的基因的表达。我们还发现，这种独特的褐变活性受S273的去磷酸化以及PPARγ配体结合区域内K268/K293的脱乙酰化的调节。基于这些数据，我们假设WAT的“褐变”受PPARγ的翻译后修饰调节，以应对个人的营养/代谢状况的变化。我们提出了三个旨在检验这一假设的目标。在AIM 1中，我们将定义为PPARγ的翻译后修饰而募集到WAT的棕色脂肪细胞的表型。在AIM 2中，我们将确定特定的翻译后修饰的PPARγ分子是否与靶基因的启动子/增强子中的某些调节元素结合。在AIM 3中，我们将确定脱磷酸化对PPARγ的K268和K293对S273或脱乙酰基化对小鼠白色脂肪组织和能量消耗的褐变的影响。确定物理效应调节PPARγ活性的分子机制将显着有助于肥胖及其与疾病相关的治疗疗法的发展。