Department of Orthopedics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China.
J Agric Food Chem. 2024 Aug 14;72(32):18013-18026. doi: 10.1021/acs.jafc.4c03677. Epub 2024 Aug 1.
Glucose and lipid metabolism dysregulation in skeletal muscle contributes to the development of metabolic disorders. The efficacy of fucoxanthin in alleviating lipid metabolic disorders in skeletal muscle remains poorly understood. In this study, we systematically investigated the impact of fucoxanthin on mitigating lipid deposition and insulin resistance in skeletal muscle employing palmitic acid-induced lipid deposition in C2C12 cells and mice. Fucoxanthin significantly alleviated PA-induced skeletal muscle lipid deposition and insulin resistance. In addition, fucoxanthin prominently upregulated the expression of lipid metabolism-related genes ( and ), promoting fatty acid β-oxidation metabolism. Additionally, fucoxanthin significantly increased the expression of and , elevated the mtDNA/nDNA ratio, and reduced ROS levels. Further, we identified pyruvate kinase muscle isozyme 1 (PKM1) as a high-affinity protein for fucoxanthin by drug affinity-responsive target stability and LC-MS and confirmed their robust interaction by CETSA, microscale thermophoresis, and circular dichroism. Supplementation with pyruvate, the product of PKM1, significantly attenuated the beneficial effects of fucoxanthin on lipid deposition and insulin resistance. Mechanistically, fucoxanthin reduced glucose glycolysis rate and enhanced mitochondrial biosynthesis and fatty acid β-oxidation through inhibiting PKM1 activity, thereby alleviating lipid metabolic stress. These findings present a novel clinical strategy for treating metabolic diseases using fucoxanthin.
葡萄糖和脂质代谢失调在骨骼肌中导致代谢紊乱的发生。褐藻黄素在缓解骨骼肌脂质代谢紊乱方面的功效尚未被充分了解。在这项研究中，我们系统地研究了褐藻黄素对棕榈酸诱导的 C2C12 细胞和小鼠骨骼肌脂质沉积和胰岛素抵抗的缓解作用。褐藻黄素显著减轻了 PA 诱导的骨骼肌脂质沉积和胰岛素抵抗。此外，褐藻黄素显著上调了脂质代谢相关基因（和）的表达，促进脂肪酸β-氧化代谢。此外，褐藻黄素显著增加了和的表达，提高了 mtDNA/nDNA 比值，并降低了 ROS 水平。进一步通过药物亲和反应靶标稳定性和 LC-MS 鉴定出丙酮酸激酶肌肉同工酶 1（PKM1）是褐藻黄素的高亲和力蛋白，并通过 CETSA、微尺度热泳动和圆二色性证实了它们的强相互作用。补充 PKM1 的产物丙酮酸显著减弱了褐藻黄素对脂质沉积和胰岛素抵抗的有益作用。机制上，褐藻黄素通过抑制 PKM1 活性降低葡萄糖糖酵解速率，增强线粒体生物合成和脂肪酸β-氧化，从而减轻脂质代谢应激。这些发现为使用褐藻黄素治疗代谢疾病提供了一种新的临床策略。
