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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