芦丁及芦丁联合运动对白色脂肪组织内质网应激、脂联素表达的影响及机制研究

Obesity and its related disorders are exerting great burden in China. It is imperative to explore economic and practical strategies in the prevention and treatment of obesity and its complications. Endoplasmic reticulum stress (ER stress) plays important pathophysiological roles in adipose tissue dysfunction. Pilot data from my laboratory suggest that rutin can induce lipolysis and the phosphorylation of AMPK. Previous findings by the applicant suggest that exercise can affect adipose tissue function such as activation of AMPK. The aim of this proposal is 1) to explore rutin, rutin in combination with exercise in the prevention and treatment of ER stress, and reduction of adiponectin expression in adipose tissue of mice challenged with high fat diet, as well as the AMPK/SIRT signaling pathway; 2) via primary culture of human adipocytes as a model, to explore rutin, rutin in combination with epinephrine on saturated fatty acids induced ER stress, reduction of adiponectin expression; by utilizing chemical antagonists combined with siRNA, to elucidate the role of AMPK/SIRT1 signaling pathway in the control of ER stress and adiponectin expression. Findings from this proposal will add evidence that rutin and exercise has additive or synergistic effects on adipose tissue function and the potential mechanisms involved in. This will provide evidence whether rutin, in combination with exercise might be promising strategies in the prevention and treatment of obesity and related disorders. Eventually this will lay theoretical foundation for implementing individualized healthy lifestyle recommendation plan in China.

肥胖及其并发症正在给我国带来沉重负担。亟需探讨经济实用的防治肥胖及其并发症的措施。内质网应激是导致脂肪组织功能紊乱的主要原因之一。芦丁是一种具有经济学优势的黄酮类化合物糖苷。申请人预实验结果提示芦丁能够诱导人脂肪细胞甘油三酯分解及AMPK磷酸化。申请人前期工作表明运动能够改善脂肪组织功能如诱导AMPK磷酸化。本课题拟探讨：① 芦丁及芦丁联合运动对高脂饮食肥胖模型小鼠脂肪组织内质网应激、脂联素表达及AMPK-SIRT1信号通路影响的预防及治疗作用；② 在原代培养的人脂肪细胞中芦丁及芦丁和肾上腺素的结合对饱和脂肪酸诱导的内质网应激、低脂联素表达的影响，及AMPK-SIRT1在控制上述效应中的作用。这将增加芦丁、运动对脂肪组织影响的协同或添加效应证据及相关机制，阐明芦丁联合运动能否成为经济有效的防治肥胖及其并发症的措施，从而为在我国推行个性化的生活方式指导方案奠定理论基础。

我国是肥胖和超重增速较快的国家之一，目前已有超过3亿的超重和肥胖人群。肥胖和超重状况下人体最显著的病理变化之一是白色脂肪组织数量的增加和功能受损。脂肪组织功能受损还会导致胰岛素抵抗、炎症反应等病理变化，从而增加糖尿病等慢性代谢性疾病的发病风险。因此探讨有效的改善肥胖状况下脂肪组织功能受损的措施及具体机制具有重要理论及现实意义。. 本课题旨在探讨研究芦丁、运动及联合干预对高脂饮食诱导的小鼠脂肪组织脂肪分解信号通路紊乱、内质网应激、脂联素及相关蛋白的影响，以及这些干预作用是否存在部位特异性。. 我们发现：1. 芦丁联合运动干预（联合干预）改善了HFD诱导的空腹血糖及胰岛素水平的升高、糖耐量及胰岛素耐量受损状况。运动及联合干预改善了睾周脂肪组织中甘油三酯分解通路的紊乱。2.芦丁、运动和联合干预有效改善了睾周脂肪组织中内质网应激状态；而在皮下脂肪组织中，各干预手段仅降低了p-JNK蛋白表达量。3.在睾周脂肪组织中，运动和联合干预改善了PPAR-γ和DsbA-L的蛋白表达量。在皮下脂肪组织中，高脂饮食却导致脂联素mRNA表达水平及PPAR-γ蛋白表达的显著升高。4.芦丁和运动干预有效增加了睾周和皮下脂肪组织中PGC-1α+β表达量。5. 各干预措施在影响脂肪组织脂肪分解信号通路、内质网应激标志物和脂联素mRNA表达和PGC-1α+β蛋白表达方面，存在部位特异性。6. 芦丁联合运动能够改善高脂饮食诱导的小鼠认知功能障碍且可能与影响IDE、BACE1、p-STAT3、p-CREB、synaptophysin、PSD-95蛋白的表达有关。. 研究结果对于芦丁、运动是否能够成为有效的肥胖防治措施提供理论依据。.