East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States.
Department of Kinesiology, East Carolina University, Greenville, NC, United States.
Front Endocrinol (Lausanne). 2021 Feb 9;11:622581. doi: 10.3389/fendo.2020.622581. eCollection 2020.
Rho-kinase 1 (ROCK1) has been implicated in diverse metabolic functions throughout the body, with promising evidence identifying ROCK1 as a therapeutic target in diabetes and obesity. Considering these metabolic roles, several pharmacological inhibitors have been developed to elucidate the mechanisms underlying ROCK1 function. Y27632 and fasudil are two common ROCK1 inhibitors; however, they have varying non-specific selectivity to inhibit other AGC kinase subfamily members and whole-body pharmacological approaches lack tissue-specific insight. As a result, interpretation of studies with these inhibitors is difficult, and alternative approaches are needed to elucidate ROCK1's tissue specific metabolic functions. Fortunately, recent technological advances utilizing molecular carriers or genetic manipulation have facilitated discovery of ROCK1's tissue-specific mechanisms of action. In this article, we review the tissue-specific roles of ROCK1 in the regulation of energy balance and substrate utilization. We highlight prominent metabolic roles in liver, adipose, and skeletal muscle, in which ROCK1 regulates energy expenditure, glucose uptake, and lipid metabolism inhibition of AMPK2α and paradoxical modulation of insulin signaling. Compared to ROCK1's roles in peripheral tissues, we also describe contradictory functions of ROCK1 in the hypothalamus to increase energy expenditure and decrease food intake leptin signaling. Furthermore, dysregulated ROCK1 activity in either of these tissues results in metabolic disease phenotypes. Overall, tissue-specific approaches have made great strides in deciphering the many critical metabolic functions of ROCK1 and, ultimately, may facilitate the development of novel treatments for metabolic disorders.
Rho 激酶 1（ROCK1）在全身各种代谢功能中都有牵连，有希望的证据表明 ROCK1 是糖尿病和肥胖症的治疗靶点。考虑到这些代谢作用，已经开发了几种药理学抑制剂来阐明 ROCK1 功能的机制。Y27632 和法舒地尔是两种常见的 ROCK1 抑制剂；然而，它们对抑制其他 AGC 激酶亚家族成员的非特异性选择性不同，全身药理学方法缺乏组织特异性见解。因此，这些抑制剂的研究结果难以解释，需要替代方法来阐明 ROCK1 的组织特异性代谢功能。幸运的是，利用分子载体或遗传操作的最新技术进步促进了 ROCK1 的组织特异性作用机制的发现。在本文中，我们综述了 ROCK1 在调节能量平衡和底物利用中的组织特异性作用。我们强调了 ROCK1 在肝脏、脂肪组织和骨骼肌中代谢作用的重要性，ROCK1 调节能量消耗、葡萄糖摄取和脂质代谢，抑制 AMPK2α 和胰岛素信号的反常调节。与 ROCK1 在周围组织中的作用相比，我们还描述了 ROCK1 在下丘脑中的相反作用，以增加能量消耗和减少食物摄入，瘦素信号。此外，这些组织中 ROCK1 活性的失调会导致代谢疾病表型。总的来说，组织特异性方法在阐明 ROCK1 的许多关键代谢功能方面取得了重大进展，最终可能有助于开发治疗代谢紊乱的新方法。
