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

• 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
• 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

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.

肥胖已经达到了流行病的比例，导致2型糖尿病发病率的急剧增加。 糖尿病和心血管疾病。肥胖个体的脂肪组织扩张是一个直接原因 由于白色脂肪（WAT）内甘油三酯（TG）的过度积累， 脂肪细胞有两种主要类型的脂肪，白色储存TG和棕色（BAT）氧化 它们产生热量。直到最近，人们还认为BAT只存在于肩胛间区域， 新生儿，但最近的几项调查已经确定BAT在宫颈，锁骨上， 成年人的腋窝和椎旁区域。BAT对静息代谢率的贡献， 动物健康体重的体内平衡现在已经很好地建立。在肥胖个体中，长期体重 只有将“adipostat”调整到一个较低的水平，才能维持亏损。参与的机制 具体情况尚不清楚，但最佳可得技术似乎发挥了重要作用。BAT是一种柔韧的组织 可以通过各种刺激来招募，包括啮齿动物和人类的寒冷暴露。事实上，许多早期 研究表明棕色脂肪细胞被募集到WAT中，以解释能量平衡的变化。 对不同效应器的反应。我们最近发现，胰岛素的合成过氧化物酶体受体配体- 致敏剂在小鼠和培养物中的白色脂肪细胞中诱导BAT功能。设立这一 brite/beige表型的过氧化物酶体增殖物激活受体涉及BAT和缺氧反应基因的选择性表达， 以及抑制与胰岛素抵抗相关的基因。我们还发现这种独特的 布朗宁活性受S273的去磷酸化以及K268/K293的去乙酰化调节， 过氧化物酶体增殖物激活受体的配体结合区。基于这些数据，我们假设WAT的“布朗宁”是 受PPAR的翻译后修饰调节，以响应营养/代谢状态的变化 个人的。我们提出了三个目标来检验这一假设。在目标1中，我们将定义 棕色样脂肪细胞对过氧化物酶体增殖物激活受体翻译后修饰的反应。在目标2中， 我们将确定特定的后修饰的PPAR分子是否与选择的调节因子结合， 靶基因的启动子/增强子中的元件。在目标3中，我们将确定 对S273的脱磷酸化或对白色脂肪布朗宁的K268和K293的脱乙酰化 组织和能量消耗。确定生理学上的分子机制 调节“布朗宁”活动的效应子将显著促进 肥胖症及其相关疾病的治疗剂。