Abstract：
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 ob/ob 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 (Pparα and Cpt-1), promoting fatty acid β-oxidation metabolism. Additionally, fucoxanthin significantly increased the expression of Pgc-1α and Tfam, 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.
摘要：
骨骼肌中葡萄糖和脂质代谢失调有助于代谢紊乱的发展。岩藻黄质在减轻骨骼肌脂质代谢紊乱中的功效仍然知之甚少。在这项研究中,我们在C2C12细胞和ob/ob小鼠中，采用棕榈酸诱导的脂质沉积，系统地研究了岩藻黄质对减轻骨骼肌脂质沉积和胰岛素抵抗的影响。岩藻黄质可显着减轻PA诱导的骨骼肌脂质沉积和胰岛素抵抗。此外,岩藻黄质显著上调脂质代谢相关基因（Pparα和Cpt-1）的表达，促进脂肪酸β-氧化代谢。此外,岩藻黄质显著增加Pgc-1α和Tfam的表达,提高了mtDNA/nDNA比率，并降低ROS水平。Further,我们通过药物亲和反应靶标稳定性和LC-MS鉴定了丙酮酸激酶肌肉同工酶1（PKM1）作为岩藻黄质的高亲和力蛋白，并通过CETSA证实了它们的强相互作用，微型热泳，和圆二色性。补充丙酮酸盐，PKM1的产物，显着减弱岩藻黄质对脂质沉积和胰岛素抵抗的有益作用。机械上,岩藻黄质通过抑制PKM1活性降低糖酵解速率,增强线粒体生物合成和脂肪酸β-氧化,从而缓解脂质代谢应激。这些发现提出了使用岩藻黄质治疗代谢疾病的新临床策略。
