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（由适用提供）：肥胖及其相关疾病，包括糖尿病和心血管疾病，在全球流行率都在增长。治疗肥胖症和糖尿病的新兴治疗途径是通过激活热脂肪细胞来增加能量消耗。这些细胞的特征是多眼脂质液滴，高线粒体含量以及产生热量的膜蛋白解偶联蛋白1（UCP1）的表达。有两种不同类型的热脂肪细胞，棕色和米色细胞。棕色或米色的脂肪供应代谢益处，至少在 啮齿动物。尽管在阐明建立和维护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的了解少得多。对这些信号分子及其作用机制的理解可能揭示了脂肪组织异质细胞环境中的新串扰，并为探索热细胞的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涉及几种创新的体内方法的开发和应用，以阐明可以激活棕色和米色脂肪细胞的新型分泌因素。在此提案中，我将检验以下假设：循环因子metrnl和pm20d1可以照亮棕色和米色脂肪生理，同时提供潜在的药物干预节点，使其干预到代谢疾病。具体而言，我建议：1）检验以下假设：Metrnl缺陷小鼠患有脂肪组织稳态扰动； 2）检验PM20D1是一种棕色/米色脂肪选择性脂肪因子的假设，可以改善代谢健康； 3）确定PM20D1促进热发生的机制。我将使用小鼠遗传学，代谢分析和生化技术的结合来解决这些问题。成功，我预计这些研究可以为 肥胖和相关代谢性疾病的治疗。我的直接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，始终牢记其出现的潜在治疗机会。我的长期职业目标是确立自己是代谢和糖尿病领域的独立研究者。在我的研究生学习期间，我亲身经历了技术进步的显着能力，以推动我们对哺乳动物生理和行为的理解的前沿。在我的博士后培训期间，这个总体主题仍然存在，并继续影响我的科学思维和计划。我计划向前看，我计划利用培训的化学和技术开发方面，专门针对肥胖和糖尿病问题。这项研究的讨论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的公认领导者。 NIH独立奖对于我向独立的过渡至关重要，因为这将使我能够在啮齿动物肥胖模型的代谢特征中获得更多的培训，同时还可以提高我将需要成功独立性的沟通，管理和写作技巧。