Healthier White Adipose by Recruitment of Beige/Brite Adipocytes

描述(申请人提供)：肥胖症已经达到大流行的程度，导致2型糖尿病和心血管疾病的发病率急剧增加。肥胖个体脂肪组织的膨胀是这些疾病的直接原因，原因是甘油三酯(TGS)在白色脂肪(WAT)脂肪细胞中过度积累。有两种主要的脂肪，白色储存TGS，棕色(BAT)氧化它们产生热量。直到最近，人们还认为蝙蝠只存在于新生儿的肩关节间区，但最近的几项研究发现，蝙蝠存在于成人的颈部、锁骨上、腋窝和椎旁区。BAT对动物静息代谢率和健康体重动态平衡的贡献现已得到证实。对于肥胖的人来说，只有将“脂肪”重新调整到较低的水平，才能维持长期的减肥。参与这一减肥的机制尚不清楚，但BAT似乎扮演着重要的角色。蝙蝠是一种灵活的组织，可以被各种刺激招募，包括在啮齿动物和人类身上暴露在寒冷中。事实上，许多早期的研究表明，棕色脂肪细胞被招募到WAT，以解释不同效应器引起的能量平衡的变化。我们最近已经证明，合成的PPARγ配体类胰岛素增敏剂在小鼠和培养的白色脂肪细胞中诱导BAT功能。通过PPARγ建立这种Brite/Beige表型包括选择性地表达BAT和低氧反应基因以及抑制与胰岛素抵抗相关的基因。我们还发现，这种独特的褐变活性受到PPARγ配体结合区S273的去磷酸化和K268/K293的去乙酰化的调节。基于这些数据，我们假设WAT的“褐变”是由PPARγ的翻译后修饰来调节的，以响应个体营养/代谢状态的变化。我们提出了三个目的来检验这一假设。在目标1中，我们将定义在WAT中招募的棕色样脂肪细胞的表型，以响应PPARγ的翻译后修饰。在目标2中，我们将确定特定的翻译后修饰的PPARγ分子是否与目标基因的启动子/增强子中的调控元件结合。目的3研究PPARγS273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。明确生理效应器调节PPARγ褐变活性的分子机制将对肥胖及其相关疾病的治疗方法的发展做出重大贡献。

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.