Novel Lipid Mobilizing Factor for Obesity

描述（由申请人提供）：肥胖是全球日益严重的主要医学问题。它是美国第二大可预防死亡原因，仅次于吸烟。目前的治疗包括饮食，运动，行为矫正，手术干预和药物干预单独或组合。然而，长期成功率很低，因此对治疗肥胖症的新方法存在重大未满足的需求。该提案的总体目标是开发一种称为脂质动员因子（IMF）的新型肽作为肥胖症的治疗方法。LMF是在进行减肥饮食的人的尿液中发现的，其基于其刺激培养的脂肪细胞中的脂解的能力。第一个目标是完全纯化LMF并确定氨基酸序列。这将使用蛋白质纯化的标准色谱程序来完成。纯化和鉴定LMF后，将通过标准肽合成程序制备合成LMF。合成LMF将与天然纯化LMF一起沿着进行检测，以确认体外活性。将测试肽在鼠3 T3-L1脂肪细胞和人脂肪细胞中对脂解的刺激。在体外证实合成LMF的活性后，将在肥胖动物模型中进行测试。突变型糖尿病（db/db）小鼠吃得过多并变得肥胖，因为它们不能对饱腹感诱导激素瘦素做出反应，这是由于瘦素受体的突变。从六周龄开始，将对小鼠注射合成LMF或媒介物对照，并监测体重增加以及食物和水消耗两个月。根据以前的结果，预计LMF将显著抑制体重增加，可能是由于能量消耗增加。两个月后，将处死动物，并分析身体组成，以确定体重增加的抑制是否是由于脂肪或瘦体重的减少。如果LMF由于脂肪量减少而抑制体重增加，则这将证明在II期研究中进行进一步评价是合理的，包括不同的肥胖动物模型、药理学和毒理学以及作用机制分析。这项研究的结果可能为治疗肥胖提供一种新的方法。

DESCRIPTION (provided by applicant): Obesity is a growing major medical problem worldwide. It is the second most important cause of preventable death in the US, exceeded only by cigarette smoking. Current treatments consist of diet, exercise, behavior modification, surgical intervention, and pharmacological intervention alone or in combination. However, long-term success rates are poor, and thus there is a major unmet need for new approaches to treat obesity. The overall goal of this proposal is to develop a novel peptide termed lipid mobilizing factor (IMF) as a therapy for obesity. LMF was discovered in the urine of humans undergoing weight-loss diets based on its ability to stimulate lipolysis in cultured adipocytes. The first aim is to completely purify LMF and determine the amino acid sequence. This will be accomplished using standard chromatographic procedures for protein purification. After purification and identification of LMF, synthetic LMF will be prepared by standard peptide synthesis procedures. Synthetic LMF will be tested along with natural purified LMF to confirm activity in vitro. The peptides will be tested for stimulation of lipolysis in murine 3T3-L1 adipocytes and in human adipocytes. After the activity of synthetic LMF has been confirmed in vitro, it will be tested in an animal model of obesity. Mutant diabetic (db/db) mice overeat and become obese because they cannot respond to the satiety-inducing hormone, leptin, due to a mutation in the leptin receptor. Starting at six weeks of age, mice will be given injections of synthetic LMF or vehicle control and will be monitored for weight gain and food and water consumption for two months. Based on previous results, it is expected that LMF will significantly inhibit weight gain, probably due to an increase in energy expenditure. After two months, animals will be sacrificed and the body composition analyzed to determine if inhibition of weight gain is due to a decrease in fat or lean body mass. If LMF inhibits weight gain due to a decrease in fat mass, this will justify further evaluation in phase II studies including different animal models of obesity, pharmacology, and toxicology, and analysis of mechanism of action. The results of this investigation may provide a new approach to treat obesity.