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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK085006-01
Application #
7764849
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
2010-03-01
Project End
2014-11-30
Budget Start
2010-03-01
Budget End
2010-11-30
Support Year
1
Fiscal Year
2010
Total Cost
$409,900
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Mazurek, Stefan; Kim, Gene H (2017) Genetic and epigenetic regulation of arrhythmogenic cardiomyopathy. Biochim Biophys Acta 1863:2064-2069
Tabit, Corey E; Coplan, Mitchell J; Spencer, Kirk T et al. (2017) Cardiology Consultation in the Emergency Department Reduces Re-hospitalizations for Low-Socioeconomic Patients with Acute Decompensated Heart Failure. Am J Med 130:1112.e17-1112.e31
Shimizu, Toru; Narang, Nikhil; Chen, Phetcharat et al. (2017) Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction. JCI Insight 2:
Zhou, Qian; Einert, Michaela; Schmitt, Hannah et al. (2016) MnTBAP increases BMPR-II expression in endothelial cells and attenuates vascular inflammation. Vascul Pharmacol 84:67-73
Shimizu, Toru; Liao, James K (2016) Rho Kinases and Cardiac Remodeling. Circ J 80:1491-8
Lennon, Frances E; Cianci, Gianguido C; Kanteti, Rajani et al. (2016) Unique fractal evaluation and therapeutic implications of mitochondrial morphology in malignant mesothelioma. Sci Rep 6:24578
Knipe, Rachel S; Tager, Andrew M; Liao, James K (2015) The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev 67:103-17
Zee, Robert Y L; Wang, Qing-Mei; Chasman, Daniel I et al. (2014) Gene variations of ROCKs and risk of ischaemic stroke: the Women's Genome Health Study. Clin Sci (Lond) 126:829-835
Liu, Ping-Yen; Lee, Po-Tseng; Chang, Wei-Ting et al. (2014) Evidence of pleiotropy by statins: leukocyte Rho kinase (ROCK) activity and pretreated statin before percutaneous coronary interventions are clinical vascular outcome predictors. Int J Cardiol 176:250-3
Miao, Yanying; Liao, James K (2014) Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother 14:173-85

Showing the most recent 10 out of 50 publications