Circulating Factors that Regulate Brown and Beige Fat

调节棕色和米色脂肪的循环因素

• 批准号: 8867716
• 负责人: Jonathan Z Long
• 金额: $ 9.15万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867716
• 关键词: Ablation; Address; Adipocytes; Adipose tissue; Adrenergic Agonists; Affect; American; Amino Acids; Award; Behavior; Biochemical; Bioinformatics; Biological Assay; Cardiovascular Diseases; Cells; Chemicals; Communication; Coupled; Data; Data Set; Development; Diabetes Mellitus; Diet; Disease; Ectopic Expression; Energy Metabolism; Environment; Enzymes; Family; Fatty acid glycerol esters; Gene Expression; Genetic; Goals; Health; Heating; Homeostasis; Hormones; Immune; Immune system; Intervention; Knockout Mice; Laboratories; Lipids; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Membrane Proteins; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mind; Mitochondria; Modeling; Molecular; Mus; Obesity; Paracrine Communication; Pathway interactions; Peptide Hydrolases; Peptide Library; Peptides; Phase; Physiological; Physiology; Portraits; Prevalence; Process; Recruitment Activity; Reporting; Research; Research Personnel; Rodent; Signal Transduction; Signaling Molecule; Stroke; Techniques; Technology; Testing; Therapeutic; Thermogenesis; Thinking; Tissues; Training; United States National Institutes of Health; Writing; base; blood glucose regulation; career; cost; experience; frontier; gain of function; improved; in vitro activity; in vivo; innovation; medical schools; member; novel; obesity treatment; post-doctoral training; preference; programs; public health relevance; skills; synthetic peptide; technology development; therapeutic target; tool; uncoupling protein 1

 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.

 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，在世界范围内日益流行。治疗肥胖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细胞。产热脂肪细胞有两种不同类型：棕色和米色。棕色或米色脂肪具有代谢益处这一观点现已得到充分证实，至少在细胞中是这样。 虽然在阐明建立和维持生热程序的转录途径方面已经取得了重大进展，但对调节棕色和米色脂肪功能的循环因子的了解却少之又少。脂肪组织异质细胞环境中的串扰，并为利用产热细胞治疗肥胖和糖尿病提供了令人兴奋的机会。我解决这个问题的方法包括开发和应用几种创新的体内方法来阐明可以激活的新型分泌因子。在本提案中，我将测试循环因子 METRNL 和 PM20D1 可以阐明棕色和米色脂肪生理学的假设，同时为代谢疾病提供潜在的药理学干预节点。假设 METRNL 缺陷小鼠扰乱了脂肪组织稳态；2) 检验 PM20D1 是一种棕色/米色脂肪选择性脂肪因子，可以改善脂肪组织稳态的假设；代谢健康；3）确定 PM20D1 促进生热的机制。如果成功，我预计这些研究可以为这些问题提供药理学上易于处理的目标。 我的近期和长期研究目标是确定调节脂肪组织生理学和稳态的分子和途径，并始终牢记潜在的治疗机会。在我的研究生学习期间，我亲身体验了技术进步推动我们对哺乳动物生理学和行为理解前沿的非凡能力，这一主题一直萦绕在我心头。在我的博士后培训期间和继续影响我的科学思维和规划，展望未来，我计划利用我的培训中的化学和技术开发方面，专门解决肥胖和糖尿病问题。哈佛医学院的 Spiegelman 博士是分子糖尿病研究领域公认的领导者，NIH 独立之路奖对于我向独立的过渡至关重要，因为它将使我能够获得啮齿类动物代谢特征方面的额外培训。肥胖模型，同时也改善我成功独立所需的沟通、管理和写作技能。