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.
Obesity is a main cause of morbidity and mortality in Western society. The precise mechanism that controls energy metabolism is not known. This research application proposes to investigate the role of an emerging signaling pathway, Rho kinase (ROCK), in fat tissues and skeletal muscle as a potential therapeutic target for preventing and treating diet-induced obesity.
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