Myeloid FoxO1 in Lipid Metabolism

摘要： 慢性低度炎症和胰岛素抵抗在肥胖和2型糖尿病中相互交织。低- 肝脏分级炎症催化疾病从良性脂肪变性进展为非酒精性脂肪变性 脂肪肝(NASH)。到目前为止，有效地将胰岛素抵抗与低度炎症联系起来的遗传因素 都是不完全的特征。在过去的十年里，我们的实验室专注于FoxO1，一种转录 将胰岛素信号整合到葡萄糖和脂肪代谢中的因子。我们证明了FoxO1变成了 这种作用导致巨噬细胞的异常激活和 饮食肥胖小鼠腹膜和组织巨噬细胞产生促炎细胞因子的实验研究 明显的糖尿病。我们还发现，髓系条件FoxO1基因敲除小鼠降低了低级别 营养过剩或内毒素引起的炎症反应，而髓系特异性FoxO1转基因小鼠则有 在相似的代谢应激条件下，全身和组织炎症增加。这些新数据 强调FoxO1在调节巨噬细胞激活和极化方面的生理重要性。我们 建议在巨噬细胞中描述胰岛素-Akt-FoxO1信号。我们的中心假设是FoxO1 整合胰岛素信号与巨噬细胞中细胞因子基因的表达，并与FoxO1失调联系 胰岛素对巨噬细胞异常激活的作用受损并使巨噬细胞极化偏向 炎症状态，导致肥胖和糖尿病的炎症和NASH。要解决这个问题 假设，我们提出了三个目标：1)确定FoxO1的生理效应--功能得与失 在巨噬细胞的胰岛素作用，炎症，脂肪变性和纤维化的髓系特异性FoxO1转基因对照。 髓系条件FoxO1基因敲除小鼠，2)FoxO1调控机制的研究 肥胖症和糖尿病患者组织中巨噬细胞的激活、极化和迁移，以及3)确定 髓系FoxO1失调在低度炎症、胰岛素抵抗、 Db/db显性糖尿病小鼠和FPC(果糖、棕榈酸酯和胆固醇)小鼠的脂肪变性和纤维化 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FoxO1失调是否可能推动 脂肪变性到纳什。我们的数据将说明FoxO1和/或其下游效应物具有潜在的治疗作用 抑制炎症以改善代谢性疾病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.