ROCK and Obesity

摇滚与肥胖

基本信息

批准号：
8387027
负责人：
JAMES Kuang-Jan LIAO
金额：
$ 30.19万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8387027
关键词：
1-Phosphatidylinositol 3-Kinase Actins Adipocytes Adipose tissue Animals Apoptosis Basal metabolic rate Biogenesis Body Weight Body fat Brain CREB1 gene Calcium Cell Adhesion Cell-Cell Adhesion Circadian Rhythms Consumption Cytokinesis Cytoskeleton Development Diet Dual-Energy X-Ray Absorptiometry Eating Embryo Energy Metabolism Exercise Exhibits Family Fasting Fatty acid glycerol esters Glucose Goals Hepatocyte In Vitro Insulin Insulin Resistance Islet Cell Laboratories Lead Lipoproteins Liver Mediating Metabolic Metabolic Diseases Metabolism Mitochondria Modality Monitor Monomeric GTP-Binding Proteins Morbidity - disease rate Motor Activity Mus Obesity Oxygen Oxygen Consumption Pancreas Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phagocytosis Phosphorylation Phosphotransferases Physical Endurance Physiological Pilot Projects Play Protein Isoforms Protein Kinase ROCK1 gene Research Resources Rho-associated kinase Role Signal Pathway Skeletal Muscle Societies Stimulus System Testing Thermogenesis Time Tissues Up-Regulation Vascular Smooth Muscle cell motility cell transformation insulin receptor substrate 1 protein insulin signaling lipid biosynthesis migration mitogen-activated protein kinase p38 mortality myogenesis novel therapeutics prevent public health relevance response rho therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The Rho-associated coiled-coil forming kinases (ROCKs) were initially identified as downstream effectors of RhoA, which mediates calcium-insensitive contraction of vascular smooth muscle. Two distinct ROCK isoforms, ROCK1 and ROCK2, have been identified, however, their role in energy metabolism and obesity are not known. In our preliminary studies, we found that despite comparable food intake, mice with hemizygous deletion of ROCK2 (ROCK2) develop insulin resistance, have 25% higher body weight, and 2 times more body fat than wild-type or ROCK1 mice. Furthermore, ROCK2 mice exhibit circadian rhythm disturbances, impaired adaptive thermogenesis, and 43% reduction in whole-body oxygen consumption; features which are similar to mice with homozygous deletion of peroxisome proliferators-activated receptor 3 co-activator (PGC)-11. These findings suggest that ROCK2 may be an important regulator of PGC-11 and energy metabolism. The overall goal of this proposal, therefore, is to investigate the role of ROCK2 in energy metabolism and obesity, and to determine the mechanism by which ROCK2 regulates PGC-11 expression and function. Specific aim 1 will test the hypothesis that deletion of ROCK2 leads to altered basal metabolism, impaired energy expenditure, and obesity. Using hemizyous ROCK1 and ROCK2 KO mice that were developed in our laboratory, we will test the hypothesis that deletion of leads to decreased energy metabolism and obesity. The effects of ROCK2 deletion on insulin, glucose, and lipoprotein metabolism will also be investigated. Specific aim 2 will test the hypothesis that PGC-11 mediates the downstream effects of ROCK2 on energy metabolism. We will determine whether conditions, which are mediated by or involve with the upregulation of PGC-11 such as the fasting state, adaptive thermogenesis, and physical endurance are defective in ROCK2 mice. Specific aim 3 will test the hypothesis that ROCK2 increases energy metabolism through induction, phosphorylation, and stabilization of PGC-11. The effects of ROCK2-mediated PGC-11 phosphorylation on mitochondrial biogenesis and energy metabolism in skeletal muscle and adipose tissues will also be investigated.

描述（由申请人提供）：最初将与Rho相关的卷曲螺旋形成激酶（岩石）鉴定为Rhoa的下游效应子，它介导了对钙不敏感的血管平滑肌的不敏感收缩。但是，已经鉴定出了两种不同的岩石同工型Rock1和Rock2，但是它们在能量代谢和肥胖症中的作用尚不清楚。在我们的初步研究中，我们发现，尽管食物摄入可比，但岩石2缺失的小鼠（Rock2）会产生胰岛素抵抗，体重高25％，体内脂肪是野生型或岩石1小鼠的2倍。此外，Rock2小鼠表现出昼夜节律障碍，自适应生热作用受损，全身消耗量降低了43％；与过氧化物酶体增殖物激活受体3共激活因子（PGC）-11相似的小鼠类似的特征。这些发现表明，Rock2可能是PGC-11和能量代谢的重要调节剂。因此，该提案的总体目标是研究Rock2在能量代谢和肥胖症中的作用，并确定Rock2调节PGC-11的表达和功能的机制。具体目标1将检验以下假设：Rock2的缺失会导致基础代谢，能量消耗受损和肥胖。使用在我们的实验室中开发的半细岩石和岩石2 KO小鼠，我们将检验以下假设，即导致能量代谢和肥胖减少的降低。还将研究Rock2缺失对胰岛素，葡萄糖和脂蛋白代谢的影响。具体目标2将检验PGC-11介导Rock2对能量代谢的下游影响的假设。我们将确定条件是由PGC-11的上调介导的，例如禁食状态，自适应生热和物理耐力在Rock2小鼠中是否有缺陷。具体目标3将检验以下假设：岩石2通过诱导，磷酸化和PGC-11的稳定来增加能量代谢。还将研究Rock2介导的PGC-11磷酸化对骨骼肌和脂肪组织中线粒体生物发生和能量代谢的影响。