Department of Internal Medicine, Division of Endocrinology, Medical School, University of Patras, Patras, Greece.
Diabetes. 2011 Oct;60(10):2465-73. doi: 10.2337/db11-0112. Epub 2011 Aug 18.
Obesity is characterized by chronic oxidative stress. Fibroblast growth factor 21 (FGF21) has recently been identified as a novel hormone that regulates metabolism. NFE2-related factor 2 (Nrf2) is a transcription factor that orchestrates the expression of a battery of antioxidant and detoxification genes under both basal and stress conditions. The current study investigated the role of Nrf2 in a mouse model of long-term high-fat diet (HFD)-induced obesity and characterized its crosstalk to FGF21 in this process.
Wild-type (WT) and Nrf2 knockout (Nrf2-KO) mice were fed an HFD for 180 days. During this period, food consumption and body weights were measured. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test. Total RNA was prepared from liver and adipose tissue and was used for quantitative real-time RT-PCR. Fasting plasma was collected and analyzed for blood chemistries. The ST-2 cell line was used for transfection studies.
Nrf2-KO mice were partially protected from HFD-induced obesity and developed a less insulin-resistant phenotype. Importantly, Nrf2-KO mice had higher plasma FGF21 levels and higher FGF21 mRNA levels in liver and white adipose tissue than WT mice. Thus, the altered metabolic phenotype of Nrf2-KO mice under HFD was associated with higher expression and abundance of FGF21. Consistently, the overexpression of Nrf2 in ST-2 cells resulted in decreased FGF21 mRNA levels as well as in suppressed activity of a FGF21 promoter luciferase reporter.
The identification of Nrf2 as a novel regulator of FGF21 expands our understanding of the crosstalk between metabolism and stress defense.
肥胖的特征是慢性氧化应激。成纤维细胞生长因子 21（FGF21）最近被确定为一种新的激素，它可以调节代谢。核因子 E2 相关因子 2（Nrf2）是一种转录因子，它在基础和应激条件下协调一系列抗氧化和解毒基因的表达。本研究探讨了 Nrf2 在长期高脂肪饮食（HFD）诱导肥胖的小鼠模型中的作用，并描述了它在这个过程中与 FGF21 的相互作用。
野生型（WT）和 Nrf2 敲除（Nrf2-KO）小鼠喂食 HFD 180 天。在此期间，测量食物摄入量和体重。通过腹腔内葡萄糖耐量试验和腹腔内胰岛素耐量试验评估葡萄糖代谢。从肝脏和脂肪组织中提取总 RNA，用于实时定量 RT-PCR。收集空腹血浆并进行血液化学分析。使用 ST-2 细胞系进行转染研究。
Nrf2-KO 小鼠部分免受 HFD 诱导的肥胖，并表现出较低的胰岛素抵抗表型。重要的是，与 WT 小鼠相比，Nrf2-KO 小鼠的血浆 FGF21 水平更高，肝脏和白色脂肪组织中的 FGF21 mRNA 水平更高。因此，Nrf2-KO 小鼠在 HFD 下改变的代谢表型与更高的 FGF21 表达和丰度有关。一致地，Nrf2 在 ST-2 细胞中的过表达导致 FGF21 mRNA 水平降低，以及 FGF21 启动子荧光素酶报告基因的活性受到抑制。
Nrf2 作为 FGF21 的一种新的调节剂的鉴定扩展了我们对代谢和应激防御之间相互作用的理解。
