Healthier White Adipose by Recruitment of Beige/Brite Adipocytes

描述（由申请人提供）：肥胖已达到流行病的程度，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扩张是这些疾病的直接原因，这是由于白色脂肪（WAT）脂肪细胞中甘油三酯（tg）的过度积累。脂肪主要有两种，储存tg的白色脂肪和氧化tg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，但最近的一些研究发现，BAT在成人的颈椎、锁骨上、腋窝和椎旁区域都有分布。BAT对动物静息代谢率和健康体重稳态的贡献现已得到充分证实。在肥胖个体中，只有将“脂肪值”重新调整到较低的水平，才能维持长期的体重减轻。参与这一过程的机制尚不清楚，但BAT似乎起着重要作用。BAT是一种灵活的组织，可以在啮齿类动物和人类的各种刺激下招募，包括冷暴露。事实上，许多早期的研究暗示棕色脂肪细胞向WAT募集，以解释不同效应物对能量平衡的影响。我们最近的研究表明，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。PPARγ建立这种白/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受PPARγ配体结合区S273的去磷酸化以及K268/K293的去乙酰化的调控。基于这些数据，我们假设WAT的“褐变”是由PPARγ的翻译后修饰调节的，以响应个体营养/代谢状态的变化。我们提出三个目标来检验这一假设。在Aim 1中，我们将定义响应PPARγ翻译后修饰而募集到WAT的棕色样脂肪细胞的表型。在Aim 2中，我们将确定特定的翻译后修饰的PPARγ分子是否结合在靶基因的启动子/增强子中选择调控元件。在Aim 3中，我们将确定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化和能量消耗的影响。确定生理效应调节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.