Role of LRP130 in brown adipocyte determination

LRP130 在棕色脂肪细胞测定中的作用

基本信息

批准号：
7659112
负责人：
Marcus P Cooper
金额：
$ 8.19万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-10 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7659112
关键词：
Adipocytes Adipose tissue Adult Behavioral Genetics Biological Assay Body Weight decreased Breeding Brown Fat Burn injury Cardiovascular Diseases Cell physiology Cells Complex Data Development Diabetes Mellitus Dreams Dyslipidemias Epidemic Family Fasting Fatty acid glycerol esters Gene Expression Genes Genetic Goals Heart Diseases Heating Human Hypertension Insulin Resistance Knockout Mice Laboratories Leigh Disease Leucine Measurement Mitochondria Molecular Mus National Health and Nutrition Examination Survey Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nucleic Acid Regulatory Sequences Obesity Oxygen Consumption Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiologic Thermoregulation Population Process Proteins Reporting Rodent Model Role Specific qualifier value Specificity Surveys Techniques Testing Therapeutic Therapeutic Intervention Thermogenesis Tissues Triglycerides United States Variant adipocyte biology adipocyte differentiation base chromatin immunoprecipitation energy balance hepatic gluconeogenesis interest nervous system disorder novel diagnostics novel therapeutics obesity treatment programs promoter transdifferentiation uncoupling protein 1

项目摘要

DESCRIPTION (provided by applicant): Obesity is a growing epidemic in the United States, and predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue is a central regulator of whole body energy balance underscoring its importance in obesity. Two major types of adipose tissue exist, white and brown, and each depot is comprised of its requisite adipocyte. White adipocytes store energy as triglycerides, while brown adipocytes dissipate their fuel stores as heat (thermogenesis). The thermogenic capacity of brown fat is believed to render it anti-obesity. In the treatment of obesity, one dream of rationale therapeutics is to formulate compounds that confer the thermogenic qualities of brown fat onto their white adipocyte counterpart. Central to achieving such a goal is a basic understanding of brown adipocyte biology. Coactivators of the PGC-1 family regulate brown adipocyte determination, however, the molecular basis for this specificity is unknown. We recently found that LRP130 specifies PGC-1? function in hepatic gluconeogenesis, and have begun to explore the role of LRP130 in brown fat development. Preliminarily data indicates a crucial role for LRP130 in brown fat determination. LRP130 regulates several PGC-1 dependent brown fat markers, including uncoupling protein 1 (Ucp1), which is important for thermogenesis and is a hallmark of brown adipocyte determination. The goal of this application is to evaluate the role of LRP130 in brown adipocyte determination, and identify its underlying transcriptional mechanisms. We postulate that LRP130 regulates a subset of PGC-1 targets important for brown adipocyte determination. Three specific aims will test the hypothesis as follows: Aim (1) Evaluate brown adipocyte determination and mitochondrial function in adipocytes deficient for LRP130. Aim (2) Evaluate brown adipocyte determination in adipocytes expressing ectopic LRP130. Aim (3) Identify the regulatory regions of the Ucp1 promoter responsive to LRP130. Completion of this project will advance the current understanding of mechanisms underlying brown adipocyte determination, and may inform the search for new diagnostic and therapeutic interventions.

描述（由申请人提供）：肥胖是美国的流行病，易于使用2型糖尿病和心血管疾病。脂肪组织是全身能量平衡的中心调节剂，强调其在肥胖症中的重要性。存在两种主要类型的脂肪组织，白色和棕色，每个仓库都由其必要的脂肪细胞组成。白色脂肪细胞将能量存储为甘油三酸酯，而棕色脂肪细胞则将其燃料储存散发为热量（热生成）。据信棕色脂肪的热能能力使其抗肥胖。在治疗肥胖症的过程中，一个理由治疗的梦想是制定化合物，将棕色脂肪的热品质赋予其白色脂肪细胞对应物。实现这样一个目标的核心是对棕色脂肪细胞生物学的基本理解。 PGC-1家族的共激活剂调节棕色脂肪细胞的测定，但是，该特异性的分子基础尚不清楚。我们最近发现LRP130指定PGC-1？在肝糖异生中起作用，并开始探索LRP130在棕色脂肪发育中的作用。初步数据表明LRP130在棕色脂肪确定中起着至关重要的作用。 LRP130调节了几种依赖PGC-1的棕色脂肪标记，包括解偶联蛋白1（UCP1），这对于热生成很重要，并且是棕色脂肪细胞测定的标志。该应用的目的是评估LRP130在棕色脂肪细胞确定中的作用，并确定其潜在的转录机制。我们假设LRP130调节PGC-1靶标的子集对于棕色脂肪细胞测定很重要。三个特定目的将检验假设如下：目标（1）评估脂肪细胞缺乏LRP130的脂肪细胞的测定和线粒体功能。 AIM（2）评估表达异位LRP130的脂肪细胞中棕色脂肪细胞的测定。目的（3）确定对LRP130响应的UCP1启动子的调节区域。该项目的完成将提高对棕色脂肪细胞确定基础机制的当前理解，并可能告知人们寻求新的诊断和治疗性干预措施。