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.

肥胖已经达到了大流行比例，导致2型事件的急剧增加 糖尿病和心血管疾病。肥胖个体中脂肪组织的扩展是直接原因 这些疾病是由于白脂肪（WAT）中甘油三酸酯（TG）的过量积累而引起的 脂肪细胞。氧化 他们产生热量。直到最近，人们认为蝙蝠仅存在于 新生儿，但最近的一些调查发现了宫颈上的蝙蝠沉积 成年人类的腋窝和副脑区。蝙蝠对静息代谢率的贡献和 现在，动物的健康体重稳态已经建立得很好。在肥胖的个体中，长期体重 只有将“脂肪仪”重新调整到较低的水平时，才能保持损失。参与的机制 该脂肪仪尚不清楚，但蝙蝠似乎起着重要作用。蝙蝠是灵活的组织 可以通过各种刺激来招募，包括啮齿动物和人类的冷暴露。实际上，许多早期 研究暗示募集棕色脂肪细胞以解释能量平衡的变化 对不同影响的响应。我们最近表明，胰岛素合成PPAR-配体类别 敏化剂在小鼠和培养物中诱导蝙蝠在白色脂肪细胞中的功能。建立这个 PPAR的Brite/米色表型涉及BAT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。我们还发现这个独特 褐变活性受S273的去磷酸化以及K268/K293的脱乙酰化的调节 PPAR的配体结合区域。基于这些数据，我们假设WAT的“褐变”是 受PPAR的翻译后修饰调节，以应对营养/代谢状态的变化 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 为了响应PPAR的翻译后修饰而招募到WAT的棕色脂肪细胞。在AIM 2中， 我们将确定特定的翻译后修改后的PPAPER分子是否结合了选择调节 靶基因的启动子/增强子中的元素。在AIM 3中，我们将确定 pPAR的S273上的去磷酸化或K268和K293的脱乙酰化对白色脂肪的褐变 小鼠的组织和能量消耗。识别生理学的分子机制 效应子调节PPAR的“褐变”活性将显着有助于发展 肥胖症及其疾病的治疗疗法。