ROCK and Obesity

描述（由申请人提供）：Rho相关卷曲螺旋形成激酶（ROCK）最初被鉴定为RhoA的下游效应物，其介导血管平滑肌的钙不敏感性收缩。两种不同的ROCK亚型，ROCK 1和ROCK 2，已被确定，然而，它们在能量代谢和肥胖中的作用尚不清楚。在我们的初步研究中，我们发现，尽管食物摄入量相当，但ROCK 2（ROCK 2）半合子缺失的小鼠会产生胰岛素抵抗，体重比野生型或ROCK 1小鼠高25%，体脂比野生型或ROCK 1小鼠高2倍。此外，ROCK 2小鼠表现出昼夜节律紊乱、适应性产热受损和全身耗氧量减少43%;这些特征与过氧化物酶体增殖物激活受体3共激活因子（PGC）-11纯合缺失的小鼠相似。这些发现表明ROCK 2可能是PGC-11和能量代谢的重要调节因子。因此，本提案的总体目标是研究ROCK 2在能量代谢和肥胖中的作用，并确定ROCK 2调节PGC-11表达和功能的机制。 具体目标1将检验ROCK 2缺失导致基础代谢改变、能量消耗受损和肥胖的假设。使用我们实验室开发的半合子ROCK 1和ROCK 2 KO小鼠，我们将测试缺失导致能量代谢降低和肥胖的假设。还将研究ROCK 2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ROCK 2对能量代谢的下游作用的假设。我们将确定由PGC-11的上调介导或涉及的条件，如禁食状态，适应性产热和身体耐力是否在ROCK 2小鼠中有缺陷。 具体目标3将检验ROCK 2通过诱导、磷酸化和稳定PGC-11来增加能量代谢的假设。ROCK 2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也将被研究。

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.