Circulating Factors that Regulate Brown and Beige Fat

 描述（由申请人提供）：肥胖及其相关疾病，包括糖尿病和心血管疾病，在世界范围内的流行率正在增长。治疗肥胖症和糖尿病的新兴治疗途径是通过激活产热脂肪细胞来增加能量消耗。这些细胞的特征是多室脂滴、高线粒体含量和产生热量的膜蛋白解偶联蛋白1（UCP 1）的表达。有两种不同类型的产热脂肪细胞，棕色和米色细胞。棕色或米色脂肪赋予代谢益处现在已经得到了很好的证实，至少在 啮齿动物虽然在阐明建立和维持产热程序的转录途径方面取得了重大进展，但对调节棕色和米色脂肪功能的循环因子知之甚少。了解这些信号分子及其作用机制可能揭示脂肪组织异质细胞环境中的新串扰，并为利用产热细胞治疗肥胖症和糖尿病提供令人兴奋的机会。我的方法，这个问题涉及的发展和应用的几个创新，在体内的方法来阐明新的分泌因子，可以激活棕色和米色脂肪细胞。在这个建议中，我将测试的假设，即循环因子METRNL和PM20 D1可以照亮棕色和米色脂肪的生理，同时提供潜在的易处理的节点干预代谢疾病。具体而言，我建议：1）测试METRNL缺陷小鼠扰乱脂肪组织稳态的假设; 2）测试PM20 D1是棕色/米色脂肪选择性脂肪因子的假设，其可以改善代谢健康;和3）确定PM20 D1促进产热的机制。我将结合小鼠遗传学、代谢分析和生物化学技术来解决这些问题。如果成功的话，我预计这些研究可以为人类提供可追踪的目标。 治疗肥胖症和相关的代谢紊乱。我的近期和长期研究目标是确定调节脂肪组织生理和稳态的分子和途径，始终牢记潜在的治疗机会。我的长期职业目标是使自己成为代谢和糖尿病领域的独立研究者。在我的研究生学习期间，我亲身体验了技术进步的非凡能力，推动了我们对哺乳动物生理学和行为的理解。在我的博士后培训期间，这个总的主题一直伴随着我，并继续影响着我的科学思维和规划。展望未来，我计划利用我的培训的化学和技术开发方面，特别是肥胖和糖尿病的问题。这项研究的指导阶段将在哈佛医学院的布鲁斯斯皮格曼博士的实验室进行。Spiegelman博士是分子糖尿病研究领域公认的领导者。美国国立卫生研究院独立之路奖对我向独立的过渡至关重要，因为它将使我能够获得啮齿动物肥胖模型代谢特征的额外培训，同时也提高了我成功独立所需的沟通，管理和写作技能。

 DESCRIPTION (provided by applicant): Obesity and its associated disorders, including diabetes and cardiovascular disease, are growing in prevalence worldwide. An emerging therapeutic avenue for treating obesity and diabetes is to augment energy expenditure by activating thermogenic adipocytes. These cells are characterized by multiloclular lipid droplets, high mitochondrial content, and the expression of a membrane protein uncoupling protein 1 (UCP1) that generates heat. There are two distinct types of thermogenic adipocytes, brown and beige cells. That brown or beige fat confers metabolic benefit is now well established, at least in rodents. While significant progress has been made towards elucidating the transcriptional pathways that establish and maintain a thermogenic program, significantly less is known about circulating factors that regulate brown and beige fat function. An understanding of these signaling molecules and their mechanisms of action may reveal novel crosstalk in the heterogeneous cellular environment of adipose tissues and provide exciting opportunities to exploit thermogenic cells for the treatment of obesity and diabetes. My approach to this problem involves the development and application of several innovative, in vivo approaches to elucidate novel secreted factors that can activate brown and beige adipocytes. In this proposal, I will test the hypothesis that the circulating factors METRNL and PM20D1 can illuminate brown and beige fat physiology while providing potentially pharmacologically tractable nodes of intervention into metabolic diseases. Specifically, I propose to: 1) test the hypothesis that METRNL-deficient mice have perturbed adipose tissue homeostasis; 2) test the hypothesis that PM20D1 is a brown/beige fat-selective adipokine that can improve metabolic health; and 3) determine the mechanism by which PM20D1 promotes thermogenesis. I will use a combination of mouse genetics, metabolic analysis, and biochemical techniques to address these questions. If successful, I anticipate that these studies can provide pharmacologically tractable targets for the treatment of obesity and associated metabolic disorders. My immediate and long-term research objectives are to identify molecules and pathways that regulate adipose tissue physiology and homeostasis, always keeping in mind the potential therapeutic opportunities as they arise. My long-term career objective is to establish myself as an independent investigator in the field of metabolism and diabetes. During my graduate studies I experienced first-hand the remarkable capacity of technological advancements to push forward the frontiers of our understanding of mammalian physiology and behavior. This general theme has remained with me during my postdoctoral training and continues to influence my scientific thinking and planning. Projecting forward, I plan to leverage the chemical and technology development aspects of my training specifically to the problems of obesity and diabetes. The mentored phase of this research will be conducted in the laboratory of Dr. Bruce Spiegelman at Harvard Medical School. Dr. Spiegelman is a recognized leader in the field of molecular diabetes research. The NIH Pathway to Independence Award will be critical for my transition to independence because it will enable me to acquire additional training in the metabolic characterization of rodent obesity models, while also improving the communication, management, and writing skills that I will require for successful independence.