ROCK and Obesity

Summary

Principal Investigator: JAMES KUANG JAN LIAO
Affiliation: Harvard University
Country: USA
Abstract: 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. 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.
Funding Period: -------------------- - -------------------2
more information: NIH RePORT

Top Publications

  1. pmc Notch signaling as an important mediator of cardiac repair and regeneration after myocardial infarction
    Yuxin Li
    Department of Advanced Cardiovascular Imaging Analysis, Nihon University School of Medicine, Tokyo 173 8610, Japan
    Trends Cardiovasc Med 20:228-31. 2010
  2. pmc Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina
    Ming Jui Hung
    Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan
    Atherosclerosis 221:521-6. 2012
  3. pmc Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis
    Qian Zhou
    Vascular Medicine Research Unit, Brigham and Women s Hospital and Harvard Medical School, Boston, MA, USA
    Circulation 126:2236-47. 2012
  4. pmc Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion
    Doug A Medvetz
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 7:e47842. 2012
  5. pmc FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2
    Ryuji Okamoto
    Vascular Medicine Research Unit, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02139, USA
    FASEB J 27:1439-49. 2013
  6. pmc Linking endothelial dysfunction with endothelial cell activation
    James K Liao
    Cardiology Section, University of Chicago, 5841 South Maryland Avenue, MC 6080, Room B608, Chicago, Illinois 60637, USA
    J Clin Invest 123:540-1. 2013
  7. pmc Elevated rho-kinase activity as a marker indicating atherosclerosis and inflammation burden in polyvascular disease patients with concomitant coronary and peripheral arterial disease
    Ming Dong
    Division of blood and circulation, School of Medicine, Shenzhen University, Shenzhen, China
    Clin Cardiol 36:347-51. 2013
  8. pmc Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation
    Haroldo A Toque
    Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912 2300, USA
    J Sex Med 10:1502-15. 2013
  9. pmc Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation
    Shin ichi Tanaka
    Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
    Arterioscler Thromb Vasc Biol 33:1591-600. 2013
  10. pmc Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis
    Naoki Sawada
    1 GCOE Program and Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan
    Antioxid Redox Signal 20:1251-67. 2014

Scientific Experts

  • Makoto Akashi
  • James K Liao
  • Qian Zhou
  • Kensuke Noma
  • Yuxin Li
  • Ryuji Okamoto
  • Chao Yung Wang
  • Takayuki Hidaka
  • Yukio Hiroi
  • Masato Kajikawa
  • Yanying Miao
  • Naoki Sawada
  • Shin ichi Tanaka
  • Ming Dong
  • Haroldo A Toque
  • Yasuki Kihara
  • Ming Jui Hung
  • Pat P Ongusaha
  • Doug A Medvetz
  • Yukihito Higashi
  • Yang Hoon Huh
  • Ryosuke Kikuchi
  • M Zhu
  • Kyosuke Takeshita
  • Masaaki Ii
  • Partha S Biswas
  • Olivier A Harari
  • Brad A Bryan
  • Kazuaki Chayama
  • Tatsuya Maruhashi
  • Shinsuke Mikami
  • Chikara Goto
  • Yumiko Iwamoto
  • Ayumu Nakashima
  • Takeshi Matsumoto
  • Akimichi Iwamoto
  • Hiroaki Shimokawa
  • Shun Kudo
  • Masaaki Ito
  • Masaya Taniguchi
  • Nobuyuki Shiba
  • Tatsuro Minami
  • Ping Yen Liu
  • Yoshimi Takai
  • Kenia P Nunes
  • Carol L Williams
  • Yoshihiro Fukumoto
  • R William Caldwell
  • R Clinton Webb
  • Xin Jiang
  • Lin Yao
  • Kotaro Nochioka
  • Bryan P Yan
  • Ruth B Caldwell
  • Chi Wen Cheng
  • Ilse Hofmann
  • Tanja Schlechter
  • Damir Khabibullin
  • Thomas N Darling
  • Li Tang Kuo
  • Karol Kaminski
  • Goo Taeg Oh
  • Hayden Huang
  • Vera P Krymskaya
  • Christoph Bode
  • Wen Jin Cherng
  • Ning I Yang
  • Martin Moser
  • Ming Yow Hung
  • Elena A Goncharova
  • Venkatesh Hariharan
  • Chao Hung Wang
  • Kunzhong Zhang
  • Yu Mei
  • Elizabeth P Henske
  • Takuhito Shoji
  • Hannah Schmitt
  • Xinbing Han
  • E S Williams
  • Koji Yamamoto
  • Toshio Kitazawa
  • Toyoaki Murohara
  • S A Shore
  • Xian Wu Cheng
  • Soeun Ngoy
  • N G Verbout
  • Takayuki Nakayama
  • Tadashi Matsushita
  • A Fedulov
  • T Shoji

Detail Information

Publications26

  1. pmc Notch signaling as an important mediator of cardiac repair and regeneration after myocardial infarction
    Yuxin Li
    Department of Advanced Cardiovascular Imaging Analysis, Nihon University School of Medicine, Tokyo 173 8610, Japan
    Trends Cardiovasc Med 20:228-31. 2010
    ..In this review, we discuss the complex mechanisms of Notch signaling and its role in cardiac repair and regeneration after myocardial infarction...
  2. pmc Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina
    Ming Jui Hung
    Department of Cardiology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan
    Atherosclerosis 221:521-6. 2012
    ..Accordingly, we investigated whether ROCK activity is an independent marker for CVA and is altered after treatment with antispastic medications...
  3. pmc Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis
    Qian Zhou
    Vascular Medicine Research Unit, Brigham and Women s Hospital and Harvard Medical School, Boston, MA, USA
    Circulation 126:2236-47. 2012
    ..Recent studies suggest that ROCK1 in macrophages and bone marrow-derived cells mediates atherogenesis. However, a similar role for ROCK2 in the pathogenesis of atherosclerosis has not been determined...
  4. pmc Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion
    Doug A Medvetz
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 7:e47842. 2012
    ....
  5. pmc FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2
    Ryuji Okamoto
    Vascular Medicine Research Unit, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02139, USA
    FASEB J 27:1439-49. 2013
    ....
  6. pmc Linking endothelial dysfunction with endothelial cell activation
    James K Liao
    Cardiology Section, University of Chicago, 5841 South Maryland Avenue, MC 6080, Room B608, Chicago, Illinois 60637, USA
    J Clin Invest 123:540-1. 2013
    ..In 1995, James Liao and colleagues published a study in the JCI demonstrating that NO is a vascular protective factor that limits endothelial activation and prevents leukocyte adhesion to the vessel wall...
  7. pmc Elevated rho-kinase activity as a marker indicating atherosclerosis and inflammation burden in polyvascular disease patients with concomitant coronary and peripheral arterial disease
    Ming Dong
    Division of blood and circulation, School of Medicine, Shenzhen University, Shenzhen, China
    Clin Cardiol 36:347-51. 2013
    ..The aim of this study was to evaluate ROCK activity as a marker of polyvascular disease...
  8. pmc Activated Rho kinase mediates diabetes-induced elevation of vascular arginase activation and contributes to impaired corpora cavernosa relaxation: possible involvement of p38 MAPK activation
    Haroldo A Toque
    Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912 2300, USA
    J Sex Med 10:1502-15. 2013
    ..Earlier studies have demonstrated involvement of ROCK pathway in the activation of arginase in endothelial cells. However, signaling pathways activated by ROCK in the penis remain unclear...
  9. pmc Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation
    Shin ichi Tanaka
    Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
    Arterioscler Thromb Vasc Biol 33:1591-600. 2013
    ..In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells...
  10. pmc Rho/Rho-associated coiled-coil forming kinase pathway as therapeutic targets for statins in atherosclerosis
    Naoki Sawada
    1 GCOE Program and Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan
    Antioxid Redox Signal 20:1251-67. 2014
    ..Also, clinical trials will need to be performed to determine whether inhibition of ROCKs, with and without statins, could lead to further reduction in atherosclerosis and cardiovascular disease. Antioxid. Redox Signal. 20, 1251-1267. ..
  11. pmc Rho-associated kinase activity is a predictor of cardiovascular outcomes
    Masato Kajikawa
    Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1 2 3 Kasumi, Minami Ku, Hiroshima 734 8551, Japan
    Hypertension 63:856-64. 2014
    ..001). Leukocyte Rho-associated kinase activity may be a new biomarker of cardiovascular events. These findings suggest that inhibition of Rho-associated kinase activity may be a therapeutic target for prevention of cardiovascular events. ..
  12. pmc Potential serum biomarkers in the pathophysiological processes of stroke
    Yanying Miao
    Department of Medicine, University of Chicago, Section of Cardiology, Chicago, IL 60637, USA
    Expert Rev Neurother 14:173-85. 2014
    ....
  13. pmc NF-κB and innate immunity in ischemic stroke
    Olivier A Harari
    Vascular Medicine Research, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Ann N Y Acad Sci 1207:32-40. 2010
    ..Here, we review the relationship between NF-κB and ischemic stroke, its role in the neurovascular unit, and discuss some animal models that suggest that this relationship is causal...
  14. pmc Role of Rho kinase isoforms in murine allergic airway responses
    M Zhu
    Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115 6021, USA
    Eur Respir J 38:841-50. 2011
    ..Ovalbumin-induced changes in lavage interleukin-13, interleukin-5 and lymphocytes were also reduced in ROCK1(+/-) mice. In conclusion, both ROCK1 and ROCK2 are important in regulating allergic airway responses...
  15. pmc Notch1 in bone marrow-derived cells mediates cardiac repair after myocardial infarction
    Yuxin Li
    Brigham and Women s Hospital, Cambridge, MA 02139, USA
    Circulation 123:866-76. 2011
    ..Notch receptors mediate binary cell fate determination and may regulate the function of BM-derived cells. However, it is not known whether Notch1 signaling in BM-derived cells mediates cardiac repair after myocardial injury...
  16. pmc Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF
    Ryosuke Kikuchi
    Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
    Lab Invest 91:691-703. 2011
    ..Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction...
  17. pmc Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice
    Masaaki Ii
    Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA
    Circulation 121:1104-12. 2010
    ....
  18. pmc RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis
    Brad A Bryan
    Schepens Eye Research Institute, Harvard Medical School, 20 Staniford St, Boston, MA 02114, USA
    FASEB J 24:3186-95. 2010
    ....
  19. pmc Increased leukocyte rho kinase (ROCK) activity and endothelial dysfunction in cigarette smokers
    Takayuki Hidaka
    Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
    Hypertens Res 33:354-9. 2010
    ..There was a significant correlation between FMD and ROCK activity (r=-0.42, P=0.035). No other variable was correlated with FMD. These findings suggest that ROCK activity is enhanced by smoking and is a predictor of endothelial function...
  20. pmc Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice
    Partha S Biswas
    Department of Medicine, Columbia University, New York, New York, USA
    J Clin Invest 120:3280-95. 2010
    ....
  21. pmc Noninvasive method for assessing the human circadian clock using hair follicle cells
    Makoto Akashi
    Research Institute for Time Studies, Yamaguchi University, Yamaguchi 753 8511, Japan
    Proc Natl Acad Sci U S A 107:15643-8. 2010
    ..Qualitative evaluation of clock gene expression in hair follicle cells, therefore, may be an effective approach for studying the human circadian clock in the clinical setting...
  22. pmc ROCK inhibition prevents fetal serum-induced alteration in structure and function of organ-cultured mesenteric artery
    Yang Hoon Huh
    Boston Biomedical Research Institute, 64 Grove St, Watertown, MA 02472, USA
    J Muscle Res Cell Motil 32:65-76. 2011
    ..There are also negative effects that a sudden withdrawal of ROCK inhibitor might cause a stronger vasoconstriction than before it was used...
  23. pmc Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease
    Qian Zhou
    Vascular Medicine Research Unit, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Trends Pharmacol Sci 32:167-73. 2011
    ..In this review we summarize current understanding of the crucial role of RhoA/ROCK pathway in the regulation of vascular function and discuss its therapeutic potential in the treatment of atherosclerosis and vascular disease...
  24. pmc A mouse model of diet-induced obesity and insulin resistance
    Chao Yung Wang
    Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan
    Methods Mol Biol 821:421-33. 2012
    ..This model has lead to many discoveries of the important signalings in obesity, such as Akt and mTOR. The chapter describes protocols for diet induced-obesity model in mice and protocols for measuring insulin resistance and sensitivity...