Irisin调控肌肉与脂肪对胰岛素敏感性的研究

Obesity manifested by excessive and ectopic accumulation of white fat is associated with high risks of Type 2 diabetes, hyperglycemia, cardiovascular diseases and cancer. The latest WHO survey (http://www.who.int/mediacentre/factsheets/fs311/en/) indicates that not only 11% of adults are obese (BMI > 30 Kg/m2) in 2008, but the trend of obesity prevalence is also on the rise. With an estimated medical cost of $147 billion in U. S. alone in 2008, obesity and its associated health disorders have become the primary social and economic burden of modern societies. The skeletal muscle plays a critical role in body energy metabolism and insulin sensitivity as it not only disposes 75% of glucose ingested from food, but also secrets several bioactive hormones that affect adipose and liver functions. The latest research from the PI's group and other groups demonstrates that muscle exercise, shivering, and hypertrophy stimulate the secretion of irisin - a newly discovered myokine (muscle hormone) that robustly converts white adipocytes to brown adipocytes. As brown adipocytes degrade lipid storage to generate heat, an increase in abundance of brown adipocytes is associated with reduced obesity and better insulin sensitivity. The proposed study investigates the signaling mechanisms regulating the production and action of irisin in muscle, and the molecular pathway underlying the effect of irisin on white adipocytes. The PI has published in recent years a series of work on muscle-fat interaction and has extensive experience to warrant the completion of the proposed work. Once the upstream and downstream signaling pathways mediating irisin secretion and function are understood, we will then be able to design therapeutic approaches to target this axis to combat the ever increasing epidemics of obesity and Type 2 diabetes.

白色脂肪堆积造成的肥胖及其紧密相关的Ⅱ型糖尿病是影响当代人类健康的重大疾患。世界卫生组织报道肥胖的发病率逐年升高(2008年为11%)，由此带来极重的医疗和社会负担。包括本研究组在内的最新研究表明运动、寒颤和肌肥大促进肌肉分泌一种新型激素(irisin)，它能把储能型白色脂肪转化为代谢活跃的棕色脂肪,从而降低脂肪和血糖含量、提高胰岛素敏感性。但是，激活irisin的上游信号通路、irisin对肌肉本身的影响(骨骼肌吸收利用体内75%的血糖，是胰岛素最重要的响应器官)及促进脂肪棕色化的分子机理仍有待阐明。本研究利用细胞和分子生物学技术、新动物模型、RNA测序和基因功能鉴定来解答这些关键问题。申请人近几年在本领域做过一些创新性工作，有丰富的经验和组织能力来保证项目的完成。研究结果对于设计药物通过促进irisin分泌或模拟irisin信号通路来达到降血糖、减肥和战胜糖尿病具有指导意义。

白色脂肪堆积造成的肥胖及其紧密相关的Ⅱ型糖尿病是影响当代人类健康的重大疾患。世卫组织报道肥胖发病率逐年升高，由此带来极重的医疗和社会负担。研究表明运动、寒颤和肌肥大促进肌肉分泌的irisin能把储能型白色脂肪转化为代谢活跃的棕色脂肪,从而降低脂肪和血糖含量、提高胰岛素敏感性。但是，激活irisin的上游信号通路、irisin对肌肉本身的影响及促进脂肪棕色化的分子机理仍有待阐明。本研究利用细胞和分子生物学技术、新动物模型、RNA测序和基因功能鉴定来解答这些关键问题。我们通过TALEN技术在国际上首次建立肌肉特异性Fndc5突变小鼠模型，并初步对其进行基因型鉴定和分析，为后期研究Fndc5在体内尤其肌肉中的的功能提供了小鼠模型，通过深入考察Fndc5基因突变对肌肉组织和脂肪组织的影响、对胰岛素敏感性的影响，发现Fndc5突变对小鼠的骨骼肌发育、生长、再生及静息状态的糖脂代谢均未见明显影响，但在运动条件下，与野生型小鼠比较，Fndc5突变小鼠糖耐量和胰岛素敏感性显著降低，摄氧量显著减少，显著限制了运动导致的白色脂肪棕色化益处,我们的研究证明Fndc5突变基于降低Ucp1等棕色化标志因子的水平而显著抑制了运动导致的白色脂肪棕色化, 进一步验证了运动刺激Fndc5裂解为可以促使储能型白色脂肪细胞向产热型棕色细胞转化的肌因子irisin,研究结果对于设计药物通过促进irisin分泌或模拟irisin信号通路来达到降血糖、减肥和战胜糖尿病具有指导意义。