Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
Int J Obes (Lond). 2012 Sep;36(9):1215-21. doi: 10.1038/ijo.2011.235. Epub 2011 Dec 13.
The pathogenesis of obesity remains incompletely understood and the exploration of the role of novel proteins in obesity may provide important insights into its causes and treatments. Here, we report a previously unidentified role for synphilin-1 in the control of food intake and body weight. Synphilin-1, a cytoplasmic protein, was initially identified as an interaction partner of alpha-synuclein, and has implications in Parkinson's disease pathogenesis related to protein aggregation.
To study the in vivo role of synphilin-1, we characterized a human synphilin-1 transgenic mouse (SP1) by assessing synphilin-1 expression, plasma parameters, food intake and spontaneous activity to determine the major behavioral changes and their consequences in the development of the obesity phenotype.
Expression of human synphilin-1 in brain neurons in SP1 mice resulted in increased food intake, body weight and body fat. SP1 mice also displayed hyperinsulinemia, hyperleptinemia and impaired glucose tolerance. Pair-feeding SP1 mice to amounts consumed by non-transgenic mice prevented the increased body weight, adiposity, hyperinsulinemia and hyperleptinemia demonstrating that these were all the consequences of increased food intake. Transgenic expression of synphilin-1 was enriched in hypothalamic nuclei involved in feeding control, and fasting-induced elevated endogenous synphilin-1 levels at these sites, suggesting that synphilin-1 is an important player in the hypothalamic energy balance regulatory system.
These studies identify a novel function of synphilin-1 in controlling food intake and body weight, and may provide a unique obesity model for future studies of obesity pathogenesis and therapeutics.
肥胖的发病机制尚不完全清楚，探索新的蛋白质在肥胖中的作用可能为其病因和治疗提供重要的见解。在这里，我们报告了 synphilin-1 在控制食物摄入和体重方面的一个以前未被识别的作用。synphilin-1 是一种细胞质蛋白，最初被鉴定为 alpha-synuclein 的相互作用伙伴，与帕金森病发病机制中与蛋白质聚集相关。
为了研究 synphilin-1 的体内作用，我们通过评估 synphilin-1 的表达、血浆参数、食物摄入和自发活动来对人类 synphilin-1 转基因小鼠（SP1）进行了特征描述，以确定主要的行为变化及其在肥胖表型发展中的后果。
SP1 小鼠脑神经元中表达的人 synphilin-1 导致食物摄入、体重和体脂肪增加。SP1 小鼠还表现出高胰岛素血症、高瘦素血症和葡萄糖耐量受损。将 SP1 小鼠的食物摄入量配对喂养给非转基因小鼠，以防止体重增加、肥胖、高胰岛素血症和高瘦素血症，这表明所有这些都是由于食物摄入增加所致。synphilin-1 的转基因表达在参与摄食控制的下丘脑核中富集，并且这些部位的禁食诱导的内源性 synphilin-1 水平升高，提示 synphilin-1 是下丘脑能量平衡调节系统中的一个重要参与者。
这些研究确定了 synphilin-1 控制食物摄入和体重的新功能，并且可能为肥胖发病机制和治疗的未来研究提供一个独特的肥胖模型。
