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比例，导致2型糖尿病和心血管疾病的发病率急剧增加。由于白色脂肪（WAT）细胞内甘油三酯（TG）的过度积累，肥胖个体中脂肪组织的扩张是这些疾病的直接原因。有两种主要类型的脂肪，白色储存TG和棕色（BAT）氧化它们产生热量。直到最近，人们还认为BAT只存在于新生儿的肩胛间区域，但最近的几项研究已经确定BAT在成年人的颈部，锁骨上，腋窝和椎旁区域的储存库。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“adipostat”重新调整到较低水平，才能维持长期的体重减轻。参与这一调整的机制尚不清楚，但BAT似乎发挥了重要作用。BAT是一种灵活的组织，可以通过各种刺激（包括啮齿动物和人类的冷暴露）来招募。事实上，许多早期的研究涉及棕色脂肪细胞的招募WAT来解释响应于不同效应物的能量平衡的变化。我们最近发现，合成的胰岛素增敏剂的PPARγ配体类诱导小鼠和培养物中白色脂肪细胞的BAT功能。通过过氧化物酶体增殖物激活物受体γ建立这种浅棕色/米色表型涉及BAT和低氧应答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，这种独特的布朗宁活性受S273的去磷酸化以及PPARγ配体结合区域内K268/K293的去乙酰化调节。基于这些数据，我们假设WAT的“布朗宁”是通过响应个体营养/代谢状态变化的PPARγ的翻译后修饰来调节的。我们提出了三个目标来检验这一假设。在目的1中，我们将定义棕色样脂肪细胞的表型，这些脂肪细胞响应于PPARγ的翻译后修饰而募集到WAT。在目标2中，我们将确定特异性后修饰的PPARγ分子是否与靶基因启动子/增强子中的选择性调控元件结合。在目的3中，我们将确定对S273的去磷酸化或对PPARγ的K268和K293的去乙酰化对小鼠白色脂肪组织的布朗宁和能量消耗的影响。明确生理效应物调控PPARγ“布朗宁”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要贡献。

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.