转录因子Nrf2在高脂饮食所致肥胖与胰岛素抵抗中的作用及机制研究

White adipose tissue (WAT) plays a critical role in maintaining glucose and lipid homeostasis and energy balance. Impaired adipogenesis and WAT dysfunction are tightly associated with insulin resistance. High fat diet is a common environmental factor for obesity and insulin resistance. Our recent study shows that Nrf2, a master regulator of cellular adaptive antioxidant response against oxidative stress, is involved in the transcriptional regulation of adipogenesis, and Nrf2-deficient mice are resistant to obesity induced by high fat diet. In addition, it has been demonstrated that Nrf2-mediated antioxidant response also participates in fibrotic process in multiple tissues. Therefore, we hypothesize that dysfunction of Nrf2, as a critical factor for adipogenesis and physiological function of WAT, especially in the context of over calorie intake, is the key mechanism by which oxidative stress and tissue fibrosis induce insulin resistance. This study attempts to investigate roles of Nrf2 in the development of high fat diet-induced obesity, adipose tissue fibrosis and insulin resistance and critical time window through using mouse model with global and adipocyte-specific Nrf2 deficiency and adipoctye cell lines with stable knock-down of Nrf2 or Keap1 gene. Successful completion of this study will provide important insight into relationship between oxidative stress and adipose tissue dysfunction caused by overnutrition, and is helpful to develop a novel strategy for the prevention and treatment of obesity and related metabolic syndrome.

白色脂肪组织在维持糖脂代谢稳态和能量平衡中至关重要，其新生障碍和功能异常与胰岛素抵抗的发生密切相关。高脂饮食是诱发肥胖及胰岛素抵抗的常见环境因素。我们最近研究发现，作为细胞适应性抗氧化应激反应的核心调节者Nrf2，参与白色脂肪细胞新生的转录调控，其表达缺失抵抗高脂饮食引起的肥胖。此外，有研究证明Nrf2介导的抗氧化应激反应还参与多种组织的纤维化过程。为此，我们假设，Nrf2是维持白色脂肪细胞新生和功能正常的关键因子，其功能缺失尤其在过度热量摄入条件下，是氧化应激及组织纤维化诱发胰岛素抵抗的关键机制。本研究拟应用全身及脂肪细胞特异性Nrf2基因敲除小鼠以及Nrf2和Keap1基因沉默脂肪细胞模型，探索Nrf2在高脂饮食所致肥胖、脂肪组织纤维化和胰岛素抵抗中的作用、机制及关键期。本研究将加深我们对氧化应激与营养过剩致脂肪功能紊乱之间关系的理解，为防治肥胖及相关疾病提供新依据。