Adipose stem cells niche in obesity

肥胖症作为一个重大的公共卫生问题和主要的可预防的问题继续升级 死因是。美国三分之一的成年人口患有肥胖症(CDC的BRFSS，2015)。令人震惊的是，78% 退伍军人中有8%患有肥胖症，这一比例明显高于普通人群。使用 超过920万人受益，肥胖及其相关疾病的成本超过17亿美元 每年为退伍军人管理局(18)。随着这一流行病的显著上升，肥胖已成为主要的 导致心血管等严重疾病发展的健康风险因素 疾病、糖尿病、中风和某些癌症。 遗传、环境、行为和社会经济因素会导致超重和 肥胖。脂肪组织是能量稳态和血糖的重要内分泌调节器 新陈代谢。需要新的脂肪细胞来储存多余的能量(摄入和支出)。 白色脂肪细胞组织，这是通过脂肪干细胞的脂肪生成过程完成的。vbl.使用 人脂肪干细胞(ASC)从瘦肉和肥胖患者中分离出来，研究表明脂肪生成是 肥胖者肥胖症和成熟脂肪细胞表现出独特的表型 与瘦的受试者相比(5，6)。肥胖伴发慢性低度炎症， 引发胰岛素抵抗和代谢综合征(7，8)。事实证明，肥胖会改变 脂肪干细胞的利基。然而，这种现象的影响和ASC利基的重要性 肥胖症还没有被机械地研究过。因此，进行了一项筛选研究，以 确定哪些基因在肥胖的ASC中表达发生改变，从而使脂肪细胞易感 导致炎症加剧。数据显示，蛋白激酶C增量I(PKCδI)增加--一个重要的 激酶在细胞分化、增殖和凋亡中的作用。数据表明，PKCδI促进 肥胖脂肪细胞的炎症。基于这些观察，我们的目标是阐明 肥胖症患者脂肪干细胞中PKCδI的表达 目的1：确定蛋白激酶CδI在促进肥胖症炎症反应中的作用：肥胖相关 炎症导致胰岛素抵抗和代谢综合征。数据显示，pkcδI是 肥胖增加，PKCδI基因敲除抑制肥胖ASC的炎症。系统化 将进行具有PKCδI得失的炎症基因的分析。目标2：确定 肥胖性ASC中PKCδI表达的调控使用ASC，数据显示NEAT1，a 非编码长的RNA，调节PKCδI的表达。潜在的分子机制 通过核糖核酸结合分析和δ检测，确定NEAT1对PKCRNA I表达的调节。 ASC中的功能研究的损失/收益。目标3：开发和验证一种新的、特异的PKCδI 体内肥胖症的抑制剂。蛋白激酶CδI在肥胖脂肪细胞中的增加及其介导的炎症 最终导致肥胖的胰岛素抵抗。沉默PKCδI可减少细胞凋亡和 肥胖脂肪细胞的炎症。新型PKCδI的药代动力学和药效学研究 特定的抑制剂将在肥胖小鼠模型中进行体内评估。 肥胖是主要的可预防的死亡原因。超重和肥胖本身并不是 致命的；然而，肥胖是促进心血管等疾病的主要疾病 疾病、糖尿病和胰岛素抵抗，以及死亡率高的癌症(9)。 PKCδI是肥胖症炎症反应的重要介质，而炎症反应是导致肥胖的重要因素。 相关的共病。药物发现部门已经开发出一种新型的、特异的pkcδI抑制剂。 这将导致一种先进的治疗策略来管理肥胖相关的疾病。

Obesity continues to escalate as a significant public health problem and as the leading preventable cause of death. One third of adult population in US is obese (CDC's BRFSS, 2015). Alarmingly, 78% of the veteran population is obese, a notably higher percent compared to general population. With over 9.2 million beneficiaries, the cost of obesity and its related diseases exceeds $1.7 billion annually for the VA (18). With this significant rising epidemic, obesity has become one of the major health risk factor that contributes to the development of severe conditions such as cardiovascular diseases, diabetes mellitus, stroke and certain cancers. Genetic, environmental, behavioral, and socioeconomic factors cause excess weight gain and obesity. Adipose tissue is an important endocrine regulator of energy homeostasis and glucose metabolism. New adipocytes are required for storage of excess energy (intake>expenditure) in the white adipocyte tissue and this is accomplished via adipose stem cells' adipogenesis process. Using human adipose stem cells (ASC) from lean and obese patients, it was showed that adipogenesis is dysregulated in obesity and mature adipocytes in obese subjects show distinctive phenotype compared to lean subjects(5, 6). Obesity is accompanied with chronic low grade inflammation which initiates insulin resistance and metabolic syndrome(7, 8). It was demonstrated that obesity changes the adipose stem cell niche. However, the impact of this phenomenon and importance of ASC niche in obesity has not been investigated mechanistically. Hence, a screening study was undertaken to identify genes whose expression is altered in obese ASC such that it renders adipocytes susceptible to increased inflammation. Data showed increase of Protein Kinase C deltaI (PKCδI) -an important kinase in cellular differentiation, proliferation and apoptosis. The data indicated that PKCδI promotes inflammation in obese adipocytes. Based on these observations, the goal is to elucidate the role of PKCδI in adipose stem cells in obesity. Aim 1: Determine the role of PKCδI in promoting inflammation in obesity: Obesity associated inflammation contributes to insulin resistance and metabolic syndrome. Data showed that PKCδI is increased in obesity and PKCδI knockdown inhibits inflammation in obese ASC. Systematic analysis of inflammatory genes with gain and loss of PKCδI will be performed. Aim 2: Determine the regulation of PKCδI expression in obese ASC. Using ASC, the data shows that NEAT1, a long noncoding RNA, regulates PKCδI expression. The molecular mechanisms underlying regulation of PKCδI expression by NEAT1 will be determined using RNA binding assays and loss/gain of function studies in ASC. Aim 3: Develop and validate a novel, specific PKCδI inhibitor in obesity in vivo. PKCδI is increased in obese adipocytes and it mediates inflammation which culminates in insulin resistance in obesity. Silencing PKCδI decreases apoptosis and inflammation in obese adipocytes. The pharmacokinetics and pharmacodynamics of a novel PKCδI specific inhibitor will be evaluated in vivo in an obese mouse model. Obesity is the leading preventable cause of death. Overweight and obesity per se are not fatal; however obesity is the predominant condition that promotes diseases such as cardiovascular disease, diabetes mellitus and insulin resistance, and cancer which have high mortality rates(9). PKCδI is an important mediator of inflammation in obesity which significantly contributes to obesity- associated co-morbidities. The drug discovery arm has developed a novel, specific PKCδI inhibitor which will lead to an advanced therapeutic strategy for management of obesity related morbidities.