KLF2 as a Regulator of Metabolic Inflammation

项目摘要/摘要 代谢炎症与肥胖诱导的胰岛素抵抗有关，胰岛素抵抗是一种由激活的组织驻留巨噬细胞介导的慢性炎症状态。这些细胞聚集在肝脏、骨骼肌和脂肪组织中，在那里它们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是至关重要的。这项建议中的研究调查了一种新的转录因子KLF2在体内调节代谢性炎症中的作用。KLF2是Kruppel类锌指转录因子家族的成员，它调节巨噬细胞的分化和功能。然而，KLF2在介导代谢性炎症中的具体作用还没有报道。初步结果表明，当动物被放入高脂饮食时，髓系中特别缺乏KLF2的动物(Mac-KLF2[Delta/Delta])会加速肥胖和胰岛素抵抗。缺乏髓系KLF2的动物会在内脏脂肪组织的间质血管部分积聚巨噬细胞，这些巨噬细胞表达高水平的促炎因子，如TNFα、IL-6和巨噬细胞趋化蛋白-1(MCP-1)。此外，将Mac-KLF2[Delta/Delta]与ApoE[-/-]杂交可增加实验性动脉粥样硬化对高脂饮食的易感性。最后，KLF2抑制NFkappaB和AP-1的转录活性，这两条中枢致炎途径聚集在许多巨噬细胞基因靶点上。这些观察结果支持了这一应用的中心假设，即巨噬细胞KLF2通过抑制NFkappaB和AP-1信号的作用来调节代谢性炎症。该方案的目的是：(1)确定改变髓系特异性KLF2表达是否影响体内代谢性炎症的发生，以及(2)确定KLF2表达调节炎性巨噬细胞激活的分子机制。总而言之，这些结果将提供关于KLF2作为代谢性炎症调节剂的作用的分子、细胞和体内的见解。

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.