The role of IKKB in linking obesity to adipose tissue inflammation and adipogene

这个项目的目标是研究IKB激酶β(IKKB)在肥胖与脂肪组织炎症和脂肪生成之间的作用。IKKB是通过激活核因子-KB来调节先天免疫和炎症的中枢协调者。肥胖与慢性低度炎症状态有关，而慢性低度炎症被认为是糖尿病和动脉粥样硬化的主要因素。转录因子核因子-KB是炎症途径的主要介质，这些途径与肥胖相关的胰岛素抵抗和动脉粥样硬化的发展有关。IKK是IKK复合体的主要催化亚基，是炎症介质规范激活核因子-KB所必需的。鉴于IKKB在调节几种细胞类型的核因子-KB介导的炎症中的明确作用，目前尚不清楚IKKB是否与肥胖诱导的脂肪细胞炎症有关。在拟议的研究中，我们将确定脂肪细胞来源的IKKB在高脂饮食诱导的肥胖、脂肪炎症和胰岛素抵抗中的作用。在该项目第一阶段支持期间的初步研究中，我们还确定了平滑肌细胞(SMC)IKKB在低密度脂蛋白受体(LDLR)缺陷小鼠肥胖相关动脉粥样硬化发展中的作用。为了删除SMC中的IKKB，我们使用了SM22-CRE转基因雄性小鼠携带KKB等位基因，并与携带KKB等位基因的雌性LDLR-/-小鼠交配。在这些研究过程中，我们做出了一个新的发现，即SMC中IKKB的缺乏使小鼠对饮食诱导的肥胖的发展具有抵抗力。初步结果表明，SM22在原代脂肪基质/血管(SV)细胞中表达，这与最近报道的SM22-CRE在分化为脂肪组织的间充质干细胞(MSCs)中的活性一致。值得注意的是，SMC IKKB缺陷小鼠的SV细胞表现出成脂能力受损。这些结果暗示了IKKB在脂肪形成调控中的一个以前未被认识到的作用。这一建议的中心假设是，HF饮食诱导的IKKB激活促进脂肪细胞分化、脂肪细胞炎症和胰岛素抵抗。在拟议的研究中，我们将定义IKKB介导的脂肪生成调控机制。我们还将确定脂肪细胞IKKB缺乏对肥胖、脂肪炎症和胰岛素抵抗的影响，以回应HF饮食。拟议的研究将阐明脂肪细胞生物学和代谢控制的新方面，并可能导致肥胖和糖尿病的新治疗靶点。

The goal of this project is to investigate the role of IKB kinase beta (IKKB), a central coordinator of innate immunity and inflammation through activation of NF-KB, in linking obesity to adipose tissue inflammation and adipogenesis. Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The transcriptional factor NF-KB is a primary mediator of inflammatory pathways that are linked to the development of obesity-associated insulin resistance and atherosclerosis. IKKB is the predominant catalytic subunit ofthe IKK complex that is required for canonical activation of NF-KB by inflammatory mediators. Given the defined role of IKKB in regulating NF-KB-mediated inflammation in several cell types, it is unclear whether IKKB contributes to obesity-induced inflammation in adipocytes. In the proposed studies, we will define the role of adipocyte-derived IKKB in high fat (HF) diet-induced obesity, adipose inflammation and insulin resistance. In preliminary studies during Phase I support of this project, we also defined the role of smooth muscle cell (SMC) IKKB in the development of obesity-associated atherosclerosis in LDL receptor (LDLR) deficient mice. To delete IKKB in SMCs, we used SM22-Cre transgenic male mice carrying floxed IKKB alleles that were mated to female LDLR-/- mice carrying floxed IKKB alleles. During the course of these studies, we made the novel finding that deficiency of IKKB in SMCs rendered mice resistant to the development of diet-induced obesity. Preliminary results demonstrate that SM22 is expressed in primary adipose stromal/vascular (SV) cells, consistent with recent reports that SM22-Cre is active in mesenchymal stem cells (MSCs) that give rise to adipose tissue. Notably, SV cells from SMC IKKB-deficient mice exhibited impaired adipogenic potential. These results implicate a previously unrecognized role of IKKB in the regulation of adipogenesis. The central hypothesis of this proposal is that HF-diet induced activation of IKKB promotes adipocyte differentiation, adipocyte inflammation, and insulin resistance. In the proposed studies, we will define mechanisms for IKKB-mediated regulation of adipogenesis. We will also define the effect of adipocyte IKKB deficiency on the development of obesity, adipose inflammation, and insulin resistance in response to a HF diet. The proposed studies will elucidate new aspects of adipocyte biology and metabolic control and may lead to novel therapeutic targets for obesity and diabetes.