Myeloid FoxO1 in Lipid Metabolism

摘要： 慢性低度炎症和胰岛素抵抗在肥胖和2型糖尿病中交织在一起。低- 肝脏中的分级炎症催化疾病从良性脂肪变性发展为非酒精性脂肪变性 脂肪性肝炎（NASH）。迄今为止，有效地将胰岛素抵抗与低度炎症联系起来的遗传因素 并不完全特征化。在过去的十年里，我们的实验室一直专注于FoxO 1，一种转录本， 整合胰岛素信号到葡萄糖和脂质代谢的因子。我们发现FoxO 1变成了 在巨噬细胞中失调，这种作用导致异常的巨噬细胞活化， 饮食性肥胖或肥胖小鼠腹腔和组织巨噬细胞中促炎细胞因子的产生 显性糖尿病我们还发现，骨髓条件性FoxO 1基因敲除小鼠的低级别 炎症反应的营养过剩或内毒素，而骨髓特异性FoxO 1转基因小鼠， 在类似的代谢应激条件下增加全身和组织炎症。这些新数据 强调FoxO 1在调节巨噬细胞活化和极化中的生理重要性。我们 提出描绘巨噬细胞中的胰岛素-Akt-FoxO 1信号传导。我们的中心假设是FoxO 1 将胰岛素信号传导整合到巨噬细胞中的细胞因子基因表达，FoxO 1失调将 胰岛素对异常巨噬细胞活化的作用受损， 炎症状态，导致肥胖和糖尿病中的炎症和NASH。为了解决这个 假设，我们提出了三个目标：1）确定FoxO 1的生理效应的增益与功能丧失 在巨噬细胞中，骨髓特异性FoxO 1转基因与 骨髓条件性FoxO 1基因敲除小鼠，2）为了表征FoxO 1调节 肥胖症和糖尿病组织中的巨噬细胞活化、极化和迁移，以及3）为了确定肥胖症和糖尿病组织中的巨噬细胞活化、极化和迁移， 骨髓FoxO 1失调对低度炎症、胰岛素抵抗的病理贡献 显性糖尿病db/db小鼠和FPC（果糖、棕榈酸盐和胆固醇）小鼠脂肪变性和纤维化 饮食诱导的NASH。我们的研究将对巨噬细胞异常激活的机制有新的认识 和极化，并解决髓系FoxO 1失调是否有责任驱动的演变， 脂肪变性到NASH。我们的数据将表征FoxO 1和/或其下游效应物作为潜在的治疗药物。 抑制炎症以改善代谢性疾病中NASH的靶点。

Abstract: Chronic low-grade inflammation and insulin resistance are intertwined in obesity and type 2 diabetes. Low- grade inflammation in liver catalyzes the disease progression from benign steatosis to nonalcoholic steatohepatitis (NASH). To date, genetic factors that effectively link insulin resistance to low-grade inflammation are incompletely characterized. During the past decade, our laboratory has focused on FoxO1, a transcription factor that integrates insulin signaling to glucose and lipid metabolism. We showed that FoxO1 becomes deregulated in macrophages and this effect contributes to abnormal macrophage activation and proinflammatory cytokine production in both peritoneal and tissue macrophages in mice with dietary obesity or overt diabetes. We also found that myeloid-conditional FoxO1 knockout mice had reduced low-grade inflammation in response to overnutrition or endotoxin, whereas myeloid-specific FoxO1-transgenic mice had increased systemic and tissue inflammation under similar metabolic stress conditions. These new data underscore the physiological importance of FoxO1 in regulating macrophage activation and polarization. We propose to delineate insulin-Akt-FoxO1 signaling in macrophages. Our central hypothesis is that FoxO1 integrates insulin signaling to cytokine gene expression in macrophages, and FoxO1 dysregulation links impaired insulin action to abnormal macrophage activation and skewed macrophage polarization toward inflammatory states, contributing to inflammation and NASH in obesity and diabetes. To address this hypothesis, we propose three aims: 1) To determine the physiological effect of FoxO1 gain- vs. loss-of-function in macrophages on insulin action, inflammation, steatosis and fibrosis in myeloid-specific FoxO1-transgenic vs. myeloid-conditional FoxO1 knockout mice, 2) To characterize the mechanisms by which FoxO1 regulates macrophage activation, polarization and migration in tissues in obesity and diabetes, and 3) To determine the pathological contribution of myeloid FoxO1 dysregulation to low-grade inflammation, insulin resistance, steatosis and fibrosis in db/db mice with overt diabetes and mice with FPC (fructose, palmitate and cholesterol) diet-induced NASH. Our studies will gain new insights into the mechanism of abnormal macrophage activation and polarization, and address whether myeloid FoxO1 dysregulation is liable for driving the evolution of steatosis to NASH. Our data will characterize FoxO1 and/or its downstream effectors as potential therapeutic targets for suppressing inflammation to ameliorate NASH in metabolic diseases.