目的:糖尿病和代谢稳态障碍可能受益于白色脂肪组织(WAT)褐变,这与线粒体裂变有关。白藜芦醇,一种膳食多酚,对与代谢疾病相关的异常表现出有益的作用。然而,目前尚不清楚白藜芦醇是否通过调节线粒体裂变导致WAT褐变。
方法:我们给db/db小鼠服用白藜芦醇(0.4%与对照组混合)12周,测量体重,口服葡萄糖耐量,胰岛素耐受,和组织学变化。通过免疫印迹法评估附睾WAT中解偶联蛋白1(UCP1)和动力蛋白相关蛋白1(DRP1)的表达。
结果:我们发现白藜芦醇改善db/db小鼠的全身葡萄糖稳态和胰岛素抵抗,这与附睾WAT中UCP1的增加有关。白藜芦醇处理的小鼠在db/db小鼠的附睾WAT中表现出更多的线粒体片段化和DRP1磷酸化增加。这些结果在体外得到进一步证实,其中白藜芦醇诱导细胞外信号调节激酶(ERK)信号激活,导致S616位点的DRP1磷酸化(p-DRP1S616)和线粒体裂变,在3T3-L1脂肪细胞中被ERK抑制剂逆转。
结论:白藜芦醇具有调节ERK和DRP1磷酸化的作用,从而促进附睾WAT的米色细胞和改善葡萄糖稳态。我们目前的研究为白藜芦醇介导的WAT褐变的潜在机制提供了新的见解,暗示它是,至少在某种程度上,通过ERK/DRP1介导的线粒体裂变。
OBJECTIVE: Diabetes mellitus and metabolic homeostasis disorders may benefit from white adipose tissue (WAT) browning, which is associated with mitochondrial fission. Resveratrol, a dietary polyphenol, exhibits beneficial effects against abnormalities related to metabolic diseases. However, it remains unknown whether resveratrol contributes to WAT browning by regulating mitochondrial fission.
METHODS: We administered resveratrol (0.4% mixed with control) to db/db mice for 12 weeks, measuring body weight, oral glucose tolerance, insulin tolerance, and histological changes. The uncoupling protein 1 (UCP1) and dynamin-related protein 1 (DRP1) expressions in the epididymal WAT were assessed via immunoblotting.
RESULTS: We found that resveratrol improved systemic glucose homeostasis and insulin resistance in db/db mice, which was associated with increased UCP1 in epididymal WAT. Resveratrol-treated mice exhibited more fragmented mitochondria and increased phosphorylation of DRP1 in the epididymal WAT of the db/db mice. These results were further confirmed in vitro, where resveratrol induced extracellular signal-regulated kinase (ERK) signaling activation, leading to phosphorylation of DRP1 at the S616 site (p-DRP1S616) and mitochondrial fission, which was reversed by an ERK inhibitor in 3T3-L1 adipocytes.
CONCLUSIONS: Resveratrol plays a role in regulating the phosphorylation of ERK and DRP1, resulting in the promotion of beige cells with epididymal WAT and the improvement of glucose homeostasis. Our present study provides novel insights into the potential mechanism of resveratrol-mediated effects on WAT browning, suggesting that it is, at least in part, mediated through ERK/DRP1-mediated mitochondrial fission.