Healthier White Adipose by Recruitment of Beige/Brite Adipocytes

肥胖症已经达到了大流行的程度，这是2型肥胖症发病率急剧上升的原因之一。 糖尿病和心血管疾病。肥胖者脂肪组织的膨胀是直接原因。 这些疾病的原因是由于甘油三酯(TGS)在白色脂肪中过度积累(Wat) 脂肪细胞。有两种主要的脂肪，白色储存TGS，棕色(BAT)氧化 以产生热量。直到最近，人们还认为蝙蝠只存在于肩关节间区。 新生儿，但最近的几项调查发现，蝙蝠在颈部，锁骨上， 成人的腋窝和椎旁区域。BAT对静息代谢率的贡献 动物健康的体重动态平衡现在已经得到了很好的证实。在肥胖者中，长期体重 损失只有在重新调整到较低水平的情况下才能维持。参与的机制 这种自述并不详细，但蝙蝠似乎扮演着重要的角色。蝙蝠是一种有弹性的组织 这可以通过各种刺激来招募，包括在啮齿动物和人类身上暴露在寒冷中。事实上，更早的时候， 研究表明棕色脂肪细胞募集到WAT以解释能量平衡的变化 对不同效应器的响应。我们最近已经证明，合成的PPAR？配体类胰岛素- 致敏剂在小鼠和培养的白色脂肪细胞中诱导BAT功能。设立这个机构 PPAR的Brite/Beige表型涉及BAT和缺氧反应基因的选择性表达，如 以及抑制与胰岛素抵抗相关的基因。我们还发现，这个独一无二的 褐变活性由S273的去磷酸化和K268/K293的去乙酰化来调节 PPAR？的配体结合区。基于这些数据，我们假设Wat的“褐变”是 由PPAR的翻译后修饰调节，以响应营养/代谢状态的变化 关于个人的。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 棕色样脂肪细胞对PPAR？翻译后修饰的反应被招募到WAT。在目标2中， 我们将确定特定的翻译后修饰的PPAR分子是否与选择的 靶基因启动子/增强子中的元件。在目标3中，我们将确定 PPAR S273去磷酸化或K268和K293去乙酰化对白色脂肪褐变的影响 小鼠的组织和能量消耗。确定生理学的分子机制 效应器调节PPAR的“褐变”活性将显著促进 肥胖症及其相关疾病的治疗学。

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.