Conjugated linoleic acid (CLA) promotes inflammation in human adipocytes

描述(申请人提供)：这项研究的长期目标是确定安全有效的饮食策略，以减少肥胖症和相关疾病的流行。一种潜在的抗肥胖化合物是共轭亚油酸(CLA)，它在全球范围内销售，用于减肥。然而，据报道，在动物和人类中有几种副作用，如高脂血症、炎症和胰岛素抵抗。因此，这种补充剂的安全性仍然值得怀疑。此外，白色脂肪组织(WAT)中负责启动对CLA治疗的炎症反应的特定细胞类型(S)，以及10，12 CLA促进脱脂的机制尚不清楚。因此，这项建议的具体目的是：1)确定WAT中哪种细胞类型(即前脂肪细胞或脂肪细胞)是10，12共轭亚油酸介导的炎症、胰岛素抵抗和脱脂的主要介质；2)确定所涉及的特定机制(S)。根据我的初步数据，在目标1中，脂肪细胞是10，12共轭亚油酸诱导的炎症、胰岛素抵抗和脱脂的主要煽动者。在AIM#2中，预计10，12共轭亚油酸通过上游激活丝裂原激活蛋白激酶(MAPK)激活激活蛋白(AP)-1来介导这些效应。为了完成目标1中提出的研究，将使用四种不同的实验模型来确定前脂肪细胞或脂肪细胞是否对10，12共轭亚油酸介导的炎症、胰岛素抵抗和脱脂负责。在AIM#2中，将使用化学抑制剂和siRNA来确定上游MAPKs和AP-1在介导10，12共轭亚油酸诱导的炎症基因表达、胰岛素抵抗和脱脂中的作用。炎症将通过测量炎症基因表达、蛋白激活以及脂肪细胞因子和前列腺素分泌到介质中来检查。胰岛素抵抗将通过测量胰岛素刺激的葡萄糖和脂肪酸摄取量来确定。这项拟议研究的基本原理是，一旦我们了解了WAT中的哪些细胞触发了CLA的炎症反应，以及这种反应是如何发生的，就可以有效地评估它作为一种控制体重的饮食方法的安全使用。这项拟议的研究对公众健康很重要，因为它将提供必要的信息，以确定安全有效的饮食策略，以减少体内脂肪和改善整体健康。整体健康状况的改善预计将减少治疗肥胖症和糖尿病所需的药物和医疗保健支出。

DESCRIPTION (provided by applicant): The long-term goal of this research is to identify safe and effective dietary strategies to reduce the prevalence of obesity and associated diseases. One potential anti-obesity compound is conjugated linoleic acid (CLA), sold woridwide for weight loss. However, several adverse side effects have been reported in animals and humans such as hyperiipidemia, inflammation, and insulin resistance. Therefore, the safety of this supplement remains questionable. Furthermore, the specific cell type(s) in white adipose tissue (WAT) responsible for initiating an inflammatory response to CLA treatment, and the mechanism by which 10,12 CLA promotes delipidation, are unknown. Therefore, the specific aims of this proposal are to 1) determine which cell type in WAT (i.e., the preadipocyte or the adipocyte) that is the major mediator of 10,12 CLA- mediated inflammation, insulin resistance, and delipidation in primary cultures of newly differentiated human adipocytes, and 2) to identify the specific mechanism(s) involved. Based on my preliminary data, it is expected in Aim #1 that adipocytes are the major instigators of 10,12 CLA-induced inflammation, insulin resistance, and delipidation. It is anticipated in Aim #2 that 10,12 CLA mediates these effects through activating activator protein (AP)-1 via upstream activation of mitogen activated protein kinases (MAPKs). To complete the proposed studies in Aim #1, four different experimental models will be employed to determine whether the preadipocyte or the adipocyte is responsible for 10,12 CLA-mediated inflammation, insulin resistance, and delipidation. In Aim #2, chemical inhibitors and siRNA will be used to determine the role of upstream MAPKs and AP-1 in mediating 10,12 CLA-induced inflammatory gene expression, insulin resistance, and delipidation. Inflammation will be examined by measuring inflammatory gene expression, protein activation, and secretion of adipocytokines and prostaglandins into the media. Insulin resistance will be determined by measuring insulin-stimulated glucose and fatty acid uptake. The rationale for the proposed research is that once we understand which cells in WAT trigger the inflammatory response by CLA and how this occurs, it's safe use as a dietary approach for weight control can be evaluated effectively. The proposed research is important to public health, because it will provide information needed to identify safe and effective dietary strategies to reduce body fat and improve overall health. The improvement of overall health is expected to reduce the amount of money spent on medications and health care needed for treating obesity and diabetes.