Zaman Vandana, Matzelle Denise, Banik Naren L, Haque Azizul
Ralph H. Johnson Veterans Administration Medical Center, 109 Bee Street, Charleston, SC 29401, USA.
Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA.
Cells. 2025 Jan 16;14(2):124. doi: 10.3390/cells14020124.
Rotenone, a naturally occurring compound derived from the roots of tropical plants, is used as a broad-spectrum insecticide, piscicide, and pesticide. It is a classical, high-affinity mitochondrial complex I inhibitor that causes not only oxidative stress, α-synuclein phosphorylation, DJ-1 (Parkinson's disease protein 7) modifications, and inhibition of the ubiquitin-proteasome system but it is also widely considered an environmental contributor to Parkinson's disease (PD). While prodromal symptoms, such as loss of smell, constipation, sleep disorder, anxiety/depression, and the loss of dopaminergic neurons in the substantia nigra of rotenone-treated animals, have been reported, alterations of metabolic hormones and hyperinsulinemia remain largely unknown and need to be investigated. Whether rotenone and its effect on metabolic peptides could be utilized as a biomarker for its toxic metabolic effects, which can cause long-term detrimental effects and ultimately lead to obesity, hyperinsulinemia, inflammation, and possibly gut-brain axis dysfunction, remains unclear. Here, we show that rotenone disrupts metabolic homeostasis, altering hormonal peptides and promoting infiltration of inflammatory T cells. Specifically, our results indicate a significant decrease in glucagon-like peptide-1 (GLP-1), C-peptide, and amylin. Interestingly, levels of several hormonal peptides related to hyperinsulinemia, such as insulin, leptin, pancreatic peptide (PP), peptide YY (PYY), and gastric inhibitory polypeptide (GIP), were significantly upregulated. Administration of rotenone to rats also increased body weight and activated macrophages and inflammatory T cells. These data strongly suggest that rotenone disrupts metabolic homeostasis, leading to obesity and hyperinsulinemia. The potential implications of these findings are vast, given that monitoring these markers in the blood could not only provide a crucial tool for assessing the extent of exposure and its relevance to obesity and inflammation but could also open new avenues for future research and potential therapeutic strategies.
鱼藤酮是一种从热带植物根部提取的天然化合物，用作广谱杀虫剂、鱼药和农药。它是一种典型的高亲和力线粒体复合物I抑制剂，不仅会导致氧化应激、α-突触核蛋白磷酸化、DJ-1（帕金森病蛋白7）修饰以及泛素-蛋白酶体系统的抑制，还被广泛认为是帕金森病（PD）的一个环境致病因素。虽然已经报道了鱼藤酮处理的动物出现前驱症状，如嗅觉丧失、便秘、睡眠障碍、焦虑/抑郁以及黑质中多巴胺能神经元的丧失，但代谢激素的改变和高胰岛素血症在很大程度上仍不清楚，需要进行研究。鱼藤酮及其对代谢肽的影响是否可作为其毒性代谢作用的生物标志物，这种毒性代谢作用可导致长期有害影响并最终导致肥胖、高胰岛素血症、炎症以及可能的肠-脑轴功能障碍，目前尚不清楚。在这里，我们表明鱼藤酮会破坏代谢稳态，改变激素肽并促进炎性T细胞的浸润。具体而言，我们的结果表明胰高血糖素样肽-1（GLP-1）、C肽和胰岛淀粉样多肽显著减少。有趣的是，几种与高胰岛素血症相关的激素肽水平，如胰岛素、瘦素、胰多肽（PP）、肽YY（PYY）和胃抑制多肽（GIP），均显著上调。给大鼠施用鱼藤酮还会增加体重，并激活巨噬细胞和炎性T细胞。这些数据有力地表明，鱼藤酮会破坏代谢稳态，导致肥胖和高胰岛素血症。鉴于监测血液中的这些标志物不仅可以为评估接触程度及其与肥胖和炎症的相关性提供关键工具，还可以为未来的研究和潜在治疗策略开辟新途径，这些发现的潜在意义非常重大。
