Mitochondrial Uncoupling as a Therapeutic Target in Obesity

线粒体解偶联作为肥胖的治疗靶点

• 批准号: 8645141
• 负责人: Patrick G Sullivan
• 金额: $ 18.31万
• 依托单位: NANO-MITE TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645141
• 关键词: 2,4-Dinitrophenol; Address; Adult; Animals; Basal metabolic rate; Biodistribution; Bioenergetics; Body Composition; Body Weight; Body Weight decreased; Body mass index; Brain; Calories; Cardiovascular Diseases; Cessation of life; Custom; Data; Devices; Diet; Dose; Epidemic; Food; Generations; Genus Hippocampus; Glucose; Goals; Health; Heart; Heating; Human; Hyperthermia; In Vitro; Indirect Calorimetry; Laboratories; Legal patent; Link; Liver; Membrane Potentials; Metabolic syndrome; Methods; Mites; Mitochondria; Modeling; Mus; Muscle; Nanomanufacturing; Obesity; Overdose; Overweight; Pathology; Phase; Pilot Projects; Production; Property; Protons; Race; Recording of previous events; Respiration; Risk; Risk Factors; Rodent Model; Series; Serum; System; Techniques; Technology; Testing; Time; Toxic effect; Uncoupling Agents; Underweight; United States; United States Food and Drug Administration; Weight; base; cardiovascular risk factor; dosage; efficacy testing; in vivo; insulin tolerance; mitochondrial membrane; nanoscale; public health relevance; sound; success; therapeutic target

DESCRIPTION (provided by applicant): Obesity is recognized as a national and global epidemic, as approximately 65% of adults in the United States are classified as overweight or obese as defined by body mass index (BMI). In fact, in the year 2000, the human race reached a historical landmark, when for the first time in history the number of adults with excess weight surpassed the number of those who were underweight. Obesity is linked with several cardiovascular risk factors cumulatively recognized as the metabolic syndrome. While obesity is associated with increased risk for metabolic syndrome and cardiovascular disease; consequently, weight loss in obese subjects has been demonstrated to reduce or reverse health risk factors. Fundamentally, irrespective of the method by which weight loss occurs, even a modest reduction in body weight has been shown to consistently reduce or reverse risk factors. In the 1930s it was recognized that increasing the body's basal metabolism using mitochondrial uncouplers, directly resulted in steady and rapid weight loss. During this period the mitochondrial uncoupler 2,4-dinitophenol (2,4-DNP) was sold over the counter as a weight-loss supplement. It is the only compound to date that has been shown to be 100% effective for weight-loss; however it was eventually pulled from the shelves by the FDA as people were routinely overdosing on the compound in an effort to increase their rate of weight loss. To overcome this challenge, we have developed and patented non-carbon-based, "self-rectifying" nano-scale devices, in which we can specifically and step-wise set the uncoupling capacity that when reached shuts the device off to further proton conductance. The goal of the current application is to further establish proof of concept and to explore the potential use of these devices to promote weight loss.

描述(申请人提供)：肥胖被认为是一种全国性和全球性的流行病，因为大约65%的美国成年人被归类为超重或肥胖，这是由身体质量指数(BMI)定义的。事实上，在2000年，人类达到了一个历史里程碑，在历史上，体重超标的成年人人数第一次超过了体重不足的人数。肥胖与几个心血管危险因素有关，这些因素累积起来被认为是代谢综合征。而肥胖与代谢综合征和心血管疾病的风险增加有关；因此，肥胖受试者的体重减轻已被证明可以减少或逆转健康风险因素。从根本上说，无论减肥的方法是什么，即使是适度的体重减轻，也被证明可以始终如一地减少或逆转风险因素。20世纪30年代，人们认识到，使用线粒体解偶联器提高身体的基础新陈代谢，直接导致稳定和快速的体重减轻。在此期间，线粒体解偶联剂2，4-二硝基苯酚(2，4-DNP)作为减肥补充剂在柜台上出售。到目前为止，它是唯一一种被证明100%有效的减肥化合物；然而，它最终被FDA下架，因为人们经常过量服用这种化合物，以努力提高他们的减肥速度。为了克服这一挑战，我们已经开发并申请了非碳基“自整流”纳米器件的专利，在这种器件中，我们可以具体和循序渐进地设置解耦能力，当达到该能力时，将关闭设备，以进一步提高质子电导。目前应用的目标是进一步建立概念证明，并探索这些设备的潜在用途，以促进减肥。