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: 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
• 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

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（由申请人提供）：肥胖已达到流行的程度，导致 2 型糖尿病和心血管疾病的发病率急剧增加。由于脂肪过度积累，肥胖个体的脂肪组织扩张是这些疾病的直接原因。白色脂肪 (WAT) 脂肪细胞内的甘油三酯 (TG) 脂肪有两种主要类型：储存 TG 的白色脂肪和氧化它们产生热量的棕色脂肪 (BAT)。直到最近，人们还认为 BAT 只存在于新生儿的肩胛间区域，但最近的几项研究发现，成年人的颈椎、锁骨上、腋窝和椎旁区域也存在 BAT 库，了解 BAT 对静息代谢率和健康身体的贡献。在肥胖个体中，体重稳态现已得到很好的证实，只有将参与此过程的机制重新调整到较低水平，才能维持长期体重减轻。脂肪细胞的详细情况尚不清楚，但 BAT 似乎发挥着重要作用，它是一种灵活的组织，可以通过各种刺激（包括啮齿类动物和人类的寒冷暴露）来募集。事实上，许多早期研究表明棕色脂肪细胞会募集到 WAT。我们最近证明，合成的 PPARγ 配体类胰岛素增敏剂可诱导小鼠白色脂肪细胞和培养物中的 BAT 功能。 PPARγ 的亮/米色表型涉及 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，我们还发现这种独特的褐变活性是通过 S273 的去磷酸化以及 K268 的去乙酰化来调节的。 /K293 位于 PPARγ 的配体结合区内，基于这些数据，我们发现 WAT 的“褐变”是由翻译后调控的。 PPARγ 的修饰响应个体营养/代谢状态的变化。在目标 1 中，我们将定义响应 PPARγ 翻译后修饰而招募到 WAT 的棕色样脂肪细胞的表型。在目标 2 中，我们将确定特定翻译后修饰的 PPARγ 分子是否与靶基因启动子/增强子中的选定调控元件结合。在目标 3 中，我们将确定其效果。 PPARγ 的 S273 去磷酸化或 K268 和 K293 去乙酰化对小鼠白色脂肪组织褐变和能量消耗的影响，确定生理效应器调节 PPARγ“褐变”活性的分子机制将极大地有助于肥胖和肥胖治疗的开发。它与疾病有关。