My research focuses on identifying the molecular mechanisms mediating the metabolic action of insulin and leptin, and the resistance to these hormones that underlies diseases such as obesity and type 2 diabetes. To identify the metabolic roles of specific molecular signals, my laboratory uses genetically engineered mouse models, in conjunction with biochemical, molecular, and physiological techniques, as well as human tissue studies to translate our findings from bench to bedside. Using these techniques, we have identified Rho-kinase as an important new regulator of glucose metabolism. Our works suggest that Rho-kinase positively regulates insulin-stimulated glucose transport and signaling via either IRS-1 serine phosphorylation or active polymerization, establishing a new mechanism for the regulation of glucose transport. Our studies also demonstrate that inhibition of Rho-kinase causes insulin resistance in vivo. In human study, our finding suggests that impaired Rho-kinase activity could contribute to the pathogenesis of insulin resistance in type 2 diabetic humans. Identification of this new insulin signaling pathway has a major impact on the understanding of the pathogenesis of diabetes and has significantly advanced the diabetes field. My lab also established a new hypothesis that Rho-kinase regulates energy balance by targeting leptin receptor signaling, suggesting Rho-kinase as a key regulator of leptin action. Indeed, deletion of Rho-kinase in hypothalamic arcuate neurons causes leptin resistance and obesity. This model provides a new mechanism that advances our understanding of central leptin action and energy homeostasis. Our recent work identified apolipoprotein J (ApoJ) as a novel anorexigenic molecule that regulates appetite and energy balance. Like leptin, ApoJ treatment causes anorexia, weight loss, and hypothalamic Stat3 activation in mice. These effects are most likely mediated by a cellular mechanism that is dependent on a physical interaction between functional leptin receptors and LRP. These researches will expand knowledge of the mechanisms underlying insulin and leptin resistance in obesity and type 2 diabetes.
1. Furukawa N, Ongusaha P, Jahng WJ, Choi CS, Kim HJ, Araki K, Lee YH, Kaibuchi K, Kahn BB, Masuzaki H, Kim JK Lee SW, Kim YB. Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metabolism 2005; 2:119-129.
2. Lee DH, Shi J, Jeoung NH, Kim MS, Zabolotny JM, Lee SW, White MF, Wei L, Kim YB. Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem 2009; 284; 11776-11780
3. Chun KH, Choi KD, Lee DH, Jung YS, Henry RR, Ciaraldi TP, Kim YB. In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes. Am J Physiol Endocrinol Metab 2011; 300:E536-542, PMCID: PMC3320261
4. Chun KH, Araki K, Jee YN, Lee DH, Oh BC, Hu Huang, Lee SW, Park KS, Zabolotny JM, Kim YB. Regulation of glucose transport by ROCK1 differs from that of ROCK2 and is controlled by actin polymerization. Endocrinology 2012;153:1649-1662
5. Huang H, Kong D, Byun KH, Ye C, Koda C, Lee DH, Oh BC, Lee SW, Zabolotny JM, Kim MS, Bjorbaek C, Lowell BB, Kim YB. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nature Neurosci 2012: 12:1392-1398
6. Huang H, Lee SH, Ye C, Lima IS, Oh BC, Lowell BB, Zabolotny JM, Kim YB. ROCK1 in AgRP neurons regulates energy expenditure and locomotor activity in male mice. Endocrinology 2013; 154:3660-3670
7. Huang H, Lee DH, Zabolotny JM, Kim YB. Metabolic actions of Rho-kinase in periphery and brain. Trends in Endocrinology and Metabolism 2013; 24:506-514, PMCID: PMC3783562
8. Gurtar AU, Chu K, Raj L, Bouley R, Lee SH, Kim YB, Dunn SE, Mandinova A, Lee SW. Identification of ROCK1 kinase as a critical regulator of Beclin1 mediated autophagy during metabolic stress. Nature Communication 2013; 4
9. Gil SY, Youn BS, Byun K, Huang H, Namkoong C, Jang PG, Lee JY, Jo YH, Kang GM, Kim HK, Shin MS, Pietrizik CU, Lee B, Kim YB*, Kim MS*. Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. Nature Communication 2013; 4:1862, *co-corresponding author
10. Lee SW, Huang H, Choi KD, Lee DH, Shi J, Chun KH, Lima IS, Zabolotny JM, Wei L, Kim YB. Adipose-specific deletion of ROCK1 isoform reveals a role for diet-induced insulin resistance. Am J Physiol Endocrinol Metab 2014; 306:E332-43