KLF2 as a Regulator of Metabolic Inflammation

KLF2 作为代谢炎症的调节剂

• 批准号: 8254121
• 负责人: Wendy Ann Goodman
• 金额: $ 4.84万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254121
• 关键词: Adipose tissue; Affect; Animals; Aorta; Apolipoprotein E; Atherosclerosis; Biochemical Pathway; Biological Assay; Blood Vessels; Cell Line; Cells; Chemotactic Factors; Chronic; Complex; Cytokine Receptors; Data; Development; Diet; Disease; Dyslipidemias; EP300 gene; Epidemic; Family; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Goals; Hypertension; Immunity; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Investigation; Laboratory Study; Lipids; Liver; MAPK8 gene; Macrophage Activation; Mediating; Mediator of activation protein; Mentors; Metabolic; Molecular; Mus; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Process; Promoter Regions; Protein Kinase; Proteins; Public Health; Regulator Genes; Reporting; Role; Scarlet Red; Sepsis; Signal Pathway; Signal Transduction; Skeletal Muscle; Staining method; Stains; Testing; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; Visceral; Zinc Fingers; abstracting; atherogenesis; base; feeding; in vivo; inhibitor/antagonist; insight; loss of function; macrophage; member; monocyte; novel; response; transcription factor; uptake

Project Summary / Abstract Metabolic inflammation is associated with obesity-induced insulin resistance, a chronic inflammatory condition mediated by activated tissue-resident macrophages. These cells accumulate in the liver, skeletal muscle and adipose tissue, where they secrete proinflammatory mediators and cause tissue dysfunction. Macrophage activation and function are under robust transcriptional control, and therefore a detailed understanding of the molecular mechanisms governing these processes is of critical importance. Studies in this proposal investigate the role of KLF2, a novel transcription factor, in modulating metabolic inflammation in vivo. KLF2 is a member of the Kruppel-like family of zinc-finger transcription factors and is known to regulate macrophage differentiation and function. However, a specific role for KLF2 in mediating metabolic inflammation has not been reported. Preliminary results demonstrate that animals specifically lacking Klf2 in the myeloid lineage (Mac-KLF2[Delta/Delta]) accelerated obesity and insulin resistance when animals are placed on a high-fat diet. Animals lacking myeloid- KLF2 develop an accumulation of macrophages in the stromal vascular fraction of visceral adipose tissue, and these macrophages express high levels of pro-inflammatory factors such as TNFalpha, IL-6, and macrophage chemoattractant protein-1 (MCP-1). Furthermore, crossing Mac-KLF2[Delta/Delta] to ApoE[-/-] confers an enhanced susceptibility to experimental atherosclerosis in response to a high fat diet. Finally, KLF2 inhibits the transcriptional activity of NFkappaB and AP-1, two central pro-inflammatory pathways which converge on numerous macrophage gene targets. These observations underlie the central hypothesis of this application that macrophage KLF2 regulates metabolic inflammation via repressive effects on NFkappaB and AP-1 signaling. The goals of this proposal are: (1) To determine if altering myeloid-specific KLF2 expression affects the development of metabolic inflammation in vivo, and (2) To determine the molecular mechanisms by which KLF2 expression regulates inflammatory macrophage activation. Collectively, these results will provide molecular, cellular, and in vivo insights regarding the role of KLF2 as a modulator of metabolic inflammation.

项目概要/摘要 代谢性炎症与肥胖引起的胰岛素抵抗有关，胰岛素抵抗是一种由活化的组织驻留巨噬细胞介导的慢性炎症状况。这些细胞积聚在肝脏、骨骼肌和脂肪组织中，在那里分泌促炎介质并导致组织功能障碍。巨噬细胞的激活和功能受到强大的转录控制，因此详细了解控制这些过程的分子机制至关重要。该提案中的研究调查了 KLF2（一种新型转录因子）在调节体内代谢炎症中的作用。 KLF2 是锌指转录因子 Kruppel 样家族的成员，已知可调节巨噬细胞的分化和功能。然而，KLF2 在介导代谢炎症中的具体作用尚未报道。初步结果表明，当动物接受高脂肪饮食时，骨髓谱系中特别缺乏Klf2的动物(Mac-KLF2Δ/Δ)会加速肥胖和胰岛素抵抗。缺乏骨髓-KLF2的动物在内脏脂肪组织的基质血管部分中产生巨噬细胞积聚，这些巨噬细胞表达高水平的促炎因子，例如TNFα、IL-6和巨噬细胞趋化蛋白-1 (MCP-1)。此外，将Mac-KLF2Δ/Δ与ApoE[-/-]杂交可增强对高脂肪饮食引起的实验性动脉粥样硬化的易感性。最后，KLF2 抑制 NFkappaB 和 AP-1 的转录活性，这两条中央促炎途径汇聚于众多巨噬细胞基因靶标上。这些观察结果奠定了本申请的中心假设的基础，即巨噬细胞 KLF2 通过对 NFkappaB 和 AP-1 信号传导的抑制作用来调节代谢炎症。该提案的目标是：(1) 确定改变骨髓特异性 KLF2 表达是否会影响体内代谢炎症的发展，以及 (2) 确定 KLF2 表达调节炎症巨噬细胞活化的分子机制。总的来说，这些结果将提供有关 KLF2 作为代谢炎症调节剂的作用的分子、细胞和体内见解。