Role of IKKβ in obesity and atherosclerosis

 描述(申请人提供)：肥胖与慢性炎症状态有关，慢性炎症被认为是糖尿病和动脉粥样硬化的主要诱因。许多参与胰岛素抵抗和动脉粥样硬化发展的炎症通路都受到IKKβ/NF-κB信号的调节。然而，IKKβ在代谢紊乱和动脉粥样硬化中的作用仍然不清楚。我们的初步研究表明，平滑肌细胞(SMC)中的IKKβ缺乏(由SM22Cre-IKKβ-Flox系统驱动)使小鼠对饮食诱导的肥胖、代谢紊乱和动脉粥样硬化的发展具有抵抗力。我们的新发现是，SM22在原代脂肪基质血管(SV)细胞中表达，IKKβ正向调节脂肪的生成，提示慢性炎症可能是高脂饮食诱导脂肪细胞分化的重要初始触发因素。我们的中心假设是IKKβ在脂肪形成和动脉粥样硬化中是必不可少的，高脂饮食诱导的IKKβ激活促进脂肪细胞分化和脂肪炎症，导致肥胖、胰岛素抵抗和动脉粥样硬化的增加。我们提出了三个具体的目标：(1)确定IKKβ在营养过剩反应中调节小鼠和人类脂肪细胞分化中的作用；(2)确定脂肪细胞IKKβ在肥胖相关的胰岛素抵抗和动脉粥样硬化发展中的作用；以及(3)确定反义寡核苷酸对IKKβ的药理抑制在饮食诱导的肥胖和动脉粥样硬化中的影响。拟议的研究将确定IKKβ在脂肪形成和动脉粥样硬化形成中的作用，并将揭示营养过剩、炎症和心脏代谢性疾病之间的关键联系。我们的研究还将为使用适当的IKKβ抑制剂作为治疗肥胖和心脏代谢性疾病的创新治疗策略提供强有力的证据。

 DESCRIPTION (provided by applicant): Obesity is associated with a state of chronic inflammation that is thought to be a major contributor to diabetes and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKKβ/NF-κB signaling. However, the role of IKKβ in metabolic disorders and atherosclerosis remains elusive. Our initial studies showed that IKKβ deficiency (driven by a SM22Cre-IKKβ- flox system) in smooth muscle cells (SMCs) rendered mice resistant to the development of diet-induced obesity, metabolic disorders, and atherosclerosis. We made the novel finding that SM22 is expressed in primary adipose stromal vascular (SV) cells and IKKβ positively regulates adipogenesis, indicating that chronic inflammation might be an important initial trigger for the adipocyte differentiation in response to high-fat diet consumption. Our central hypothesis is that IKKβ is essential for adipogenesis and atherogenesis, and that high-fat diet-induced IKKβ activation promotes adipocyte differentiation and adipose inflammation, leading to increased obesity, insulin resistance, and atherosclerosis. Three specific aims are proposed: (1) Define the role of IKKβ in the regulation of murine and human adipocyte differentiation in response to overnutrition; (2) Determine the contribution of adipocyte IKKβ to the development of obesity-associated insulin resistance and atherosclerosis; and (3) Determine the impact of pharmacological inhibition of IKKβ by antisense oligonucleotides on diet-induced obesity and atherosclerosis. The proposed studies will define the role of IKKβ in adipogenesis and atherogenesis and will reveal a critical link between overnutrition, inflammation, and cardiometabolic disease. Our studies will also provide strong evidence for use of appropriate IKKβ inhibitors as an innovative therapeutic strategy to treat obesity and cardiometabolic disease.