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Energy Expenditure and Metabolic Effects through Brown/Beige Adipose Clk2 Kinase

棕色/米色脂肪 Clk2 激酶的能量消耗和代谢效应

基本信息

批准号：
9902407
负责人：
Pere Puigserver
金额：
$ 46.37万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902407
关键词：
Adipocytes Adipose tissue Affect Anti-Obesity Agents Applications Grants Biochemical Bioenergetics Body Weight CREB1 gene Cardiovascular Diseases Cell Line Cells Complex Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Diabetes Mellitus Diet Energy Intake Energy Metabolism Epidemic Exhibits Failure Fatty acid glycerol esters Funding Gene Expression Genes Genetic Transcription Goals Grant High Fat Diet Human Incidence Insulin Insulin Resistance Knockout Mice Liver Malignant Neoplasms Mediating Medical Metabolic Metabolic Diseases Mitochondria Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome Study Oxygen Consumption Pathology Patients Peripheral Pharmaceutical Preparations Phosphorylation Phosphotransferases Physical activity Predisposition Process Protein Kinase Proteins Proteome Regimen Research Respiration Signal Transduction Site Skeletal Muscle Slice Symptoms Testing Therapeutic Thermogenesis Tissues Translating Weight Gain bariatric surgery base blood glucose regulation cold temperature diabetic experimental study feeding genetic approach improved in vivo in vivo evaluation insulin signaling loss of function metabolic profile new therapeutic target novel prevent programs protein activation respiratory response uncoupling protein 1

项目摘要

Abstract Obesity and associated metabolic diseases including type 2 diabetes is a current epidemic in the US and worldwide. There are no current safe anti-obesity drugs available and bariatric surgery, in combination with dietary and physical activity regimens, is considered the best option to treat obese patients. Thus, there is an urgent medical need to identify new therapeutic targets and develop new and safer drugs to treat obesity. Defects in energy expenditure in response to diet or lower temperatures cause obesity. A major site of energy expenditure is the brown or beige adipose tissue that contains thermogenic mitochondria equipped to uncouple respiration and produce heat. The presence in humans of these thermogenic adipocytes opens up the possibility to activate them and protect against obesity. In the previous funded period we have found that deficiency of the protein Clk2, a kinase downstream of feeding signals and insulin, in adipose tissue decreases energy expenditure and exacerbates body weight upon high fat diet feeding. Clk2-deficient brown adipocytes exhibit a failure in thermogenic function associated with low levels of Uncoupling protein 1. However, the regulatory components and mechanisms of how the feeding-regulated Clk2 kinase activity affects cold- and diet-induced thermogenic activity in brown and beige adipose cells and control whole body energy expenditure are unknown. The major goal of this grant renewal is to identify and analyze the molecular and regulatory mechanism whereby the protein kinase Clk2 activates thermogenic function in brown/beige adipose tissue in response to cold and diet and increases energy expenditure to protect against obesity and diabetes. The research strategy is focused on three central aims: 1) Molecular and functional analysis of how Clk2 kinase controls thermogenic gene expression programs in brown/beige adipose cells (Specific Aim 1), 2) Cellular, metabolic and bioenergetic analysis mediated by Clk2 kinase action in adipose cells and fat tissues ex vivo (Specific Aim 2) and, 3) In vivo metabolic and energetic analysis driven by Clk2 kinase in cold- and diet- induced thermogenesis (Specific Aim 3). The outcomes from these studies will identify novel molecular mechanisms and regulatory components by which brown and beige adipocytes control rates of energy expenditure and protect against diet-induced obesity. Since insufficient energy expenditure is a hallmark of obesity and associated pathologies, our studies may translate into potential therapies.

摘要肥胖和相关的代谢疾病，包括2型糖尿病，是目前在美国流行的疾病，国际吧目前没有安全的抗肥胖药物可用，减肥手术，结合饮食和身体活动方案，被认为是治疗肥胖患者的最佳选择。因此，迫切的医疗需求是确定新的治疗靶点，并开发新的更安全的药物来治疗肥胖症。对饮食或较低温度反应的能量消耗缺陷导致肥胖。一个主要的能源场所消耗是棕色或米色的脂肪组织，含有产热线粒体，呼吸并产生热量。人体内这些产热脂肪细胞的存在，激活它们并防止肥胖的可能性。在上一个供资期间，我们发现，脂肪组织中蛋白Clk 2（摄食信号和胰岛素下游的激酶）的缺乏降低了能量消耗并加重高脂肪饮食喂养时的体重。Clk 2缺陷型棕色脂肪细胞表现出与低水平解偶联蛋白1相关的产热功能失效。但调节成分和机制，如何喂养调节Clk 2激酶活性影响冷，饮食诱导的棕色和米色脂肪细胞产热活动，并控制全身能量消耗是未知的。这项资助更新的主要目标是识别和分析分子和调节蛋白激酶Clk 2激活棕色/米色脂肪组织产热功能的机制对寒冷和饮食的反应，并增加能量消耗，以防止肥胖和糖尿病。的研究策略集中于三个中心目标：1）Clk 2激酶如何控制棕色/米色脂肪细胞中的产热基因表达程序（特异性目的1），2）细胞，离体脂肪细胞和脂肪组织中Clk 2激酶作用介导的代谢和生物能量分析（具体目标2）和，3）在寒冷和饮食中由Clk 2激酶驱动的体内代谢和能量分析。诱导产热（具体目标3）。这些研究的结果将确定新的分子棕色和米色脂肪细胞控制能量速率的机制和调节成分预防饮食引起的肥胖。由于能量消耗不足是一个标志，肥胖和相关的病理，我们的研究可能转化为潜在的治疗。