We have identified Rho-Kinase (ROCK) as a novel regulator of insulin action and glucose homeostasis. Specifically, ROCK directly regulates IRS-1 function by phosphorylating serine residues. Inhibition of ROCK function results in a reduction of insulin-stimulated glucose transport and insulin signaling, leading to insulin resistance. We found that ROCK1 deficiency causes systemic insulin resistance in vivo by impairing insulin signaling in skeletal muscle. Furthermore, insulin-stimulated ROCK activity is decreased in the skeletal muscle of obese diabetic mice and humans, suggesting that defective ROCK activity may contribute to the pathogenesis of insulin resistance. We thus hypothesize that activation of ROCK1 is critical for the metabolic action of insulin on glucose transport and insulin signaling through IRS-1 serine phosphorylation. The overall objective of this proposal is to define the novel role of ROCK1 in the regulation of glucose metabolism and insulin signaling.
Aim 1 works to determine the role of IRS-1 serine phosphorylation in ROCK1-dependent glucose metabolism. We will systemically investigate how ROCK1 controls insulin- mediated glucose metabolism via affecting IRS-1 serine phosphorylation. This will be achieved by reintroducing IRS-1 mutants in IRS-1-deficient cells and mice.
Aim 2 further elucidates the molecular mechanism in which ROCK1 is a key regulator of insulin action on glucose transport and downstream signaling. We will use small RNA interference and adenovirus gene-transfer strategies to determine the fundamental basis underlying insulin-induced activation of ROCK1 in insulin-sensitive cells or specific cell lines in which ROCK1 or IRS-1 has been deleted.
Aim 3 defines the role of ROCK1 in whole-body glucose homeostasis and insulin sensitivity in insulin-target tissues. We have successfully generated loxP flanked ROCK1 mice, which are currently being breed with mice expressing MCK-Cre or adiponectin-Cre recombinase producing muscle- or adipose-specific ROCK1-deficient mice. These mice will be characterized for whole-body insulin sensitivity and glucose homeostasis, with important implications for strategies to prevent diabetes. These studies provide a unique opportunity to identify a novel molecular mechanism in which ROCK1 is important as a critical node in insulin control of metabolism, and may offer a novel target for the treatment of diabetes and obesity.
Insulin resistance is a major risk factor for type 2 diabetes, and the cause of this is not fully understood. Preliminary data show that the inhibition of the ROCK1 function results in a decreased insulin response, leading to insulin resistance. The goal of the study is to determine the biological function of ROCK1 in insulin control of glucose metabolism, and these experiments could lead to the identification of a potential target for new diabetes drugs.
|Wang, Hye Jin; Park, Jae Yeo; Kwon, Obin et al. (2015) Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction. Autophagy 11:2089-2101|
|Zandi, Souska; Nakao, Shintaro; Chun, Kwang-Hoon et al. (2015) ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep 10:1173-86|
|Dagon, Yossi; Mantzoros, Christos; Kim, Young-Bum (2015) Exercising insulin sensitivity: AMPK turns on autophagy! Metabolism 64:655-7|
|Koo, Young Do; Choi, Jin Woo; Kim, Myungjin et al. (2015) SUMO-Specific Protease 2 (SENP2) Is an Important Regulator of Fatty Acid Metabolism in Skeletal Muscle. Diabetes 64:2420-31|
|Lee, Seung-Hwan; Huang, Hu; Choi, Kangduk et al. (2014) ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance. Am J Physiol Endocrinol Metab 306:E332-43|
|Giménez-Cassina, Alfredo; Garcia-Haro, Luisa; Choi, Cheol Soo et al. (2014) Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab 19:272-84|
|Macedo, Maria Paula; Lima, Inês S; Gaspar, Joana M et al. (2014) Risk of postprandial insulin resistance: the liver/vagus rapport. Rev Endocr Metab Disord 15:67-77|
|Dong, Huansheng; Huang, Hu; Yun, Xinxu et al. (2014) Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 155:818-28|
|Huang, Hu; Lee, Seung Hwan; Ye, Chianping et al. (2013) ROCK1 in AgRP neurons regulates energy expenditure and locomotor activity in male mice. Endocrinology 154:3660-70|
|Gurkar, Aditi U; Chu, Kiki; Raj, Lakshmi et al. (2013) Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress. Nat Commun 4:2189|
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