Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Abstract

Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

ROCK1 deficiency preserves caveolar compartmentalization of signaling molecules and cell membrane integrity

“…Of note, regarding the impact of ROCK activity on insulin signaling, multiple mechanisms have been described including actin-cytoskeleton dependent mechanism or direct interactions of ROCKs with IR signaling components. 67 While our findings point to the importance of ROCK1-mediated actin cytoskeleton remodeling on regulating caveolar IR activation, other studies support a role of ROCK1-mediated actin cytoskeleton dynamics in regulating IRS1 phosphorylation and insulin-dependent glucose transport in cultured adipocytes and muscle cells. 68 It is thus possible that ROCK1-mediated actin cytoskeleton remodeling regulates IR signaling at multiple levels in a cell-type and tissue-dependent manner.…”

“…Further studies are needed to determine whether ROCK1 regulates caveolar structure and functions in other cell types, especially in those with high abundance of caveolae and high expression of ROCK1. Of note, regarding the impact of ROCK activity on insulin signaling, multiple mechanisms have been described including actin‐cytoskeleton dependent mechanism or direct interactions of ROCKs with IR signaling components 67 . While our findings point to the importance of ROCK1‐mediated actin cytoskeleton remodeling on regulating caveolar IR activation, other studies support a role of ROCK1‐mediated actin cytoskeleton dynamics in regulating IRS1 phosphorylation and insulin‐dependent glucose transport in cultured adipocytes and muscle cells 68 .…”

“…While future studies using conditional ROCK2 deficient mice or cells are needed to address this question, our previous data suggest that ROCK2 may play a different role compared to ROCK1 in cardiomyocytes, adipocytes and MEFs. We have reported that ROCK isoforms play different roles in regulating insulin signaling and actin cytoskeleton organizations in adipocytes 21 , 30 , 67 and MEFs. 17 , 18 Specifically, different from ROCK1‐deficient adipose tissues, insulin‐stimulated IR activation was not increased the adipose tissues of ROCK2 +/− mice, in which increased insulin signaling was mediated through downstream increased IRS1‐mediated PI3K activation.…”

Addition of ROCK Inhibitors Alleviates Prostaglandin-Induced Inhibition of Adipogenesis in 3T3L-1 Spheroids

“…Among these, PG-induced suppression of adipogenesis has begun to draw a lot of attention as a possible DUES etiology in the ophthalmology field. In addition, a significant contribution of ROCK signaling toward lipid adipogenesis has also been suggested [ 16 ]. That is, it was shown that the Rho/ROCK signaling pathway negatively regulates adipocyte differentiation, in which several underlying mechanisms, including a mechanism mediated by WNT genes, the regulation of actinomyosin formation, which is a key determinant of adipogenesis, the inhibition of the insulin requirement, and others have been suggested.…”

“…Alternatively, it is also well known that Rho kinases (ROCKs), major downstream effectors of small GTPase RhoA [ 12 , 13 , 14 , 15 ], represent another pivotal regulatory factor modulating adipogenesis. In fact, the ROCK family, including ROCK1 and ROCK2, has recently attracted interest as a potential therapeutic target for the treatment of metabolic disorders, based upon the fact that upregulated ROCK activity is involved in the pathogenesis of nearly all of the metabolic syndromes including obesity, insulin resistance, dyslipidemia and hypertension [ 16 ].…”