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：
8710827
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710827
关键词：
2,4-thiazolidinedione 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 Goals Healthcare Heating 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 Obesity Outcome Peroxisome Proliferator-Activated Receptors Phenotype Phenylalanine Phosphorylation Phosphorylation Inhibition Physiological Play Post-Translational Protein Processing Process Protein Dephosphorylation Proteins RNA Recruitment Activity Regulation Regulatory Element Research Design Rodent Role Serine Stimulus Supraclavicular Testing Therapeutic Thiazolidinediones Tissues Triglycerides United States angiogenesis base combat 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

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 PPAR¿ ligand class of insulin- sensitizers induces BAT functions in white adipocytes in mice and in culture. Establishment of this brite/beige phenotype by PPAR¿ 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 PPAR¿. Based on these data, we hypothesize that the "browning" of WAT is regulated by post-translational modifications of PPAR¿ 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 PPAR¿. In Aim 2, we will determine whether specific post-translationally modified PPAR¿ 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 PPAR¿ on browning of white adipose tissue and energy expenditure in mice. Identifying the molecular mechanisms by which physiological effectors regulate the "browning" activity of PPAR¿ will significantly contribute to the development of therapeutics for obesity and it associated disorders.

肥胖已达到流行病的程度，导致 2 型肥胖的发病率急剧增加肥胖个体脂肪组织的扩张是糖尿病和心血管疾病的直接原因。这些疾病的发生是由于白色脂肪 (WAT) 中甘油三酯 (TG) 的过度积累造成的脂肪细胞主要有两种类型：储存 TG 的白色脂肪细胞和氧化的棕色脂肪细胞 (BAT)。直到最近，人们还认为 BAT 只存在于肩胛间区域。新生儿，但最近的几项研究发现，BAT 库存在于颈部、锁骨上、成年人的腋窝和椎旁区域。 BAT 对静息代谢率和代谢率的贡献。动物的健康体重稳态现已在肥胖个体中建立。只有将“脂肪调节剂”重新调整到较低水平，才能维持损失。这种脂肪抑制物尚不清楚，但 BAT 似乎发挥着重要作用。事实上，在啮齿类动物和人类中，许多刺激都可以通过各种刺激（包括寒冷暴露）来招募。研究表明棕色脂肪细胞被招募到 WAT 中来解释能量平衡的变化我们最近表明，合成的 PPAR¿胰岛素配体类别- 敏化剂诱导小鼠白色脂肪细胞和培养物中的 BAT 功能。 PPAR 的 brite/beige 表型涉及 BAT 和缺氧反应基因的选择性表达以及与胰岛素抵抗相关的基因的抑制我们还发现了这种独特的作用。褐变活性由 S273 的去磷酸化以及 K268/K293 的去乙酰化调节 PPAR的配体结合区¿基于这些数据，我们敢说WAT的“褐变”是。受 PPAR 翻译后修饰调节响应营养/代谢状态的变化我们提出了三个目标来检验这个假设，在目标 1 中，我们将定义个体的表型。响应 PPAR 翻译后修饰而招募到 WAT 的棕色样脂肪细胞¿ .在目标2中，我们将确定特定的翻译后修饰 PPAR 是否存在？分子结合选择调节在目标 3 中，我们将确定目标基因的启动子/增强子中的元素。 PPAR 的 S273 去磷酸化或 K268 和 K293 脱乙酰化¿白色脂肪褐变确定小鼠的组织和能量消耗的分子机制。效应器调节 PPAR 的“褐变”活性¿将极大地促进发展肥胖及其相关疾病的治疗。