镁补充结合低氧训练对肥胖小鼠糖脂代谢的交互作用机制研究

Our previous study of magnesium intake and the risk of metabolic syndrome has been recognized internationally. As a result, a patent application of magnesium fortified sports drink is currently underway. Also, our previous study indicates that hypoxic training significantly improves glucose and lipid metabolism. In addition, our preliminary data suggest a synergistic effect of serum magnesium levels and hypoxic training on weight loss. However, the molecular mechanism of this joint effect is unknown. Studies suggest that the three ‘lipid-sensing’ peroxisome proliferator–activated receptors (PPAR-α, PPAR-γ and PPAR-δ) regulate diverse aspects of lipid and glucose homeostasis. Thus, we hypothesize that the joint effect of magnesium supplementation and hypoxic training on weight loss are mediated by modulating PPARs. Hypoxic training increases the production of PGC-1α and HIF-1α and facilitates PPAR-γ activation, while magnesium supplementation promotes PPAR-γ phosphorylation. After the activation of PPARs, PPAR-γ alters the release of signaling molecules from fat, including leptin, tumor necrosis factor-α (TNF-α), resistin and adiponectin, which through serum transport have far-reaching metabolic effects in other tissues. Activation of this metabolic pathway improves insulin sensitivity. At the same time, PPAR-α and PPAR-δ will promote fatty acid oxidation and insulin sensitivity in muscles and the liver. The proposed study aims to determine the joint effect of magnesium supplementation and hypoxic training on glucose and lipid metabolism in high-fat-diet induced obese mice using the state of the art techniques such as co-immunoprecipitation, Western blot, and liquichip, and PPAR-γ knockout. Findings from the proposed study may be helpful to identify an optimal way for weight control, and ultimately prevention and therapy of obesity and diabetes.

课题组有关“镁与代谢综合征关系”的研究得到国际认可，结合前期“低氧训练显著改善糖脂代谢”研究结果，首次证实：血清镁浓度高低直接影响低氧训练减控体重效果。但镁摄入和低氧训练交互作用分子机制未明。我们假设：低氧训练可增加PGC-1α、HIF-1α产生，有利于激活PPAR-γ；镁可促进PPAR-γ的磷酸化。因此，两者分别从质和量层面激活PPAR-γ，进而改变从脂肪组织释放入血的信号分子浓度，改善肝脏和肌肉中胰岛素的敏感性。本研究应用分子生物学实验技术，观察镁补充结合低氧训练对肥胖小鼠脂肪组织、肝、骨骼肌PPARs及糖脂代谢的影响，并使用脂肪组织PPAR-γ基因敲除进行验证。该研究将填补国内外空白，对阐明镁补充与低氧训练对糖脂代谢交互作用的分子机制意义重大，并为低氧训练结合营养措施减控体重的"绿色"方法提供理论基础，为肥胖相关疾病的防治提供新思路。

维持离子稳态对疾病防治至关重要，近些年来，国内外学者在Cell、Nature Communication等国际顶级期刊上报道SLC39A14、PIEZO1、MgtE等离子通道参与调节体内金属离子稳态，为代谢性疾病的干预提供了新的靶点。金属离子稳态在运动改善代谢性疾病过程中发挥的作用及内在机制尚不明确。.基于本课题人体实验研究发现，肥胖青少年镁缺乏达82.4％，且低血镁影响了低氧训练的减重效果。因此首先探究不同剂量镁补充对肥胖小鼠糖脂代谢的影响，发现高剂量镁补充（200mg/kg/d）可更好改善糖脂代谢紊乱；接下来探讨高剂量镁补充结合低氧训练调控肥胖机体糖脂代谢的作用机制。但在干预期间发现高剂量镁补充后肥胖小鼠存在轻微腹泻现象，考虑到动物福利及今后在人群研究中的应用，我们深入优化实验方案，重复低剂量镁补充（100mg/kg/d）结合低氧训练动物实验，确认低剂量镁补充结合低氧训练对肥胖小鼠代谢表型的影响，并探讨镁补充、低氧训练可能的协同作用。.结果发现：（1）高剂量镁补充改善肥胖小鼠代谢表型的效果优于低剂量镁补充，并伴随血糖血脂代谢和肝脏、骨骼肌脂质代谢紊乱的改善；（2）高剂量镁补充结合低氧训练、低剂量镁补充结合低氧训练均可改善肝脏、骨骼肌、脂肪组织糖脂代谢紊乱，转录组测序结果与表型结果关联分析发现其改善肝脏脂代谢的部分机制可能通过上调PPAR信号通路实现，但镁补充、低氧训练不存在协同作用；（3）低剂量镁补充改善肥胖小鼠肝细胞损伤、改善肝脏脂代谢可能通过上调IR-Akt胰岛素信号通路，增加脂肪分解，改善肝脏脂代谢。.综上研究表明低氧训练、镁补充结合低氧训练可部分通过上调PPAR信号通路改善肝脏脂代谢表型；低剂量镁补充可能通过IR-Akt胰岛素信号通路，增加肝脏脂解，改善肝细胞损伤及肝脏脂代谢，为镁补充应用于肥胖人群改善脂肪肝提供重要理论依据。