Mitochondrial-targeted CoQ analogs: Bioenergetic Effects in Obesity

描述（由申请人提供）： 肥胖是一个主要的全球性健康问题，在我们的退伍军人中非常普遍。治疗选择有限。生活方式的改变是有效的，但难以实施，现有的药物是最低限度的有效性和/或不安全。手术治疗可能是有效的，但需要大手术，并与几个长期并发症。 尽管迄今为止药物治疗存在问题，但我们相信有一种有趣的方法需要进一步评估。该方法是用诱导轻度呼吸解偶联的试剂靶向线粒体。如在本申请的主体中所讨论的，线粒体解偶联具有将热量摄入转移到热产生而不是能量储存为脂肪质量的潜力。虽然剧烈的脱钩可能是危险的，但轻度脱钩（随着时间的推移）可能会以一种类似于运动的方式安全减肥。 辅酶Q（CoQ）被认为是一种抗氧化剂和代谢活性化合物，对健康有益。然而，辅酶Q不能或很难穿透线粒体膜，并且尚未证明有效。因此，已经尝试将CoQ靶向线粒体。一种常见的方法是缩短CoQ侧链并添加由带正电荷的阳离子三苯基膦（TPP）组成的共价连接。这导致了我们称为脑靶向辅酶Q类似物（MTQA）的化合物。原型是化合物米托醌（MitoQ），它已被开发为神经靶向抗氧化剂，目前正在研究用于治疗神经退行性疾病，衰老，肝脂肪变性和其他疾病。 在最近VA支持的工作中，我的实验室发现MTQA的显著代谢效应。考虑到线粒体靶向，这似乎并不奇怪。然而，迄今为止，对检查这些代谢产物的兴趣相对较少。 适用于治疗目的的效果。在迄今为止的初步和已发表的工作中，我们发现MTQA表现出诱导培养细胞中线粒体呼吸解偶联的剂量依赖性效应。而且，我们有初步证据表明，它们对预防小鼠肥胖有效。有些令人惊讶的是，我们有数据表明，这不仅是通过增加能量消耗，而且还通过抑制中枢神经系统水平的能量摄入。这使我们得出了一个总体假设，即在线粒体水平上起作用的MTQA化合物可以以最小的毒性预防肥胖，并最终证明 足够临床使用。简而言之，本申请的三个具体目的是：1.根据培养细胞中的代谢研究，检查选定MTQA化合物的治疗潜力。我们建议检查MitoQ、SKQ 1以及代表MitoQ和SKQ 1但每个母体化合物具有两个侧链修饰的化合物（总共六种化合物）。2.评价2-3种选定化合物在肥胖啮齿动物模型中的作用，注意对能量消耗和能量摄入的影响。3.选择1-2种化合物进行更详细的机制研究，旨在了解目标2中观察到的体内效应。意义和创新：退伍军人肥胖的临床重要性是显而易见的。我们处理这一问题的方法是创新的。我们将采用新的和创新的方法来寻找以前未发现的造成中期质量保证影响的机制，这一点将变得越来越清楚。我们指出，我们对MTQA的商业开发没有兴趣，因此，对任何一种特定化合物没有偏见。我们的兴趣是在科学方面的温和解偶联作为一种可能的治疗肥胖。

DESCRIPTION (provided by applicant): Obesity is a major worldwide health problem and highly prevalent among our veteran population. Therapeutic options are limited. Lifestyle change is effective but difficult to implement and available drugs are minimally effective and/or unsafe. Surgical therapy can be effective, but requires a major operation and is associated with several long-term complications. In spite of the problems with drug therapy to date, we believe there is an intriguing approach that needs further evaluation. That approach is to target mitochondria with agents that induce mild respiratory uncoupling. As discussed in the body of this application, mitochondrial uncoupling has the potential to divert caloric intake to heat production rather to energy storage as fat mass. Although vigorous uncoupling is likely dangerous, mild uncoupling (over time) could lead to safe weight loss in a manner that has been likened to exercise. Coenzyme Q (CoQ) has been advocated as an antioxidant and metabolically active compound offering health benefits. However, CoQ does not, or very poorly, penetrates mitochondrial membranes and has not proven effective. Therefore, attempts have been made to target CoQ to mitochondria. A common approach is to shorten the CoQ side chain and add a covalent attachment consisting of the positively charged cation, triphenylphosphonium (TPP). This has led to compounds we refer to as mitochondrial-targeted CoQ analogs (MTQAs). The prototype is the compound, mitoquinone (MitoQ), which has been developed as a mitochondrial-targeted antioxidant and is now under investigation for the treatment of neurodegenerative diseases, aging, hepatic steatosis, and other disorders. In recent VA supported work, my laboratory has found prominent metabolic effects of MTQAs. This does not seem surprising, given the mitochondrial targeting. However, to date, there has been relatively little interest in examining these metabolic effects as applicable for therapeutic purposes. In preliminary and published work to date, we found that MTQAs manifest dose-dependent effects to induce mitochondrial respiratory uncoupling in cultured cells. Moreover, we have preliminary evidence that they are effective in preventing obesity in mice. Somewhat surprisingly, we have data suggesting that this occurs, not only through enhanced energy expenditure, but also by inhibiting energy intake at the level of the central nervous system. This has led us to an overall hypothesis that a MTQA compound acting at the mitochondrial level can prevent obesity with minimal toxicity, and, ultimately, prove sufficient for clinical use. Briefly stated, the three specific aims of this application are: 1. Examine the effects of selected MTQA compounds for therapeutic potential based on metabolic studies in cultured cells. We propose to examine MitoQ, SKQ1, and compounds representing MitoQ and SKQ1 but with two side chain modifications for each parent compound (six compounds total). 2. Evaluate 2-3 selected compounds for their actions in a rodent model of obesity with attention to effects on energy expenditure and energy intake. 3. Select 1-2 compounds for more detailed mechanistic study directed at understanding the in vivo effects observed in aim 2. Significance and Innovation: The clinical importance of obesity among veterans is obvious. Our approach to addressing this issue is innovative. As will become clear, we will apply new and innovative methodology to look for previously unidentified mechanisms underlying the effects of MTQAs. We point out that we have no interest in the commercial development of MTQAs and, therefore, no bias towards any one particular compound. Our interest is in the scientific aspects of mild uncoupling as a possible treatment for obesity.