Roles of Ras Homolog Guanosine Triphosphate Phosphohydrolases in Adipocyte Differentiation, Insulin Signaling, and Lipid Droplet Dynamics

Abstract

Ras homolog guanosine triphosphate phosphohydrolases (Rho GTPases), a family of small GTPases, are important players in many physiological processes such as cytoskeleton remodeling. Emerging experimental results have indicated them as pivotal regulators of lipid metabolism, which has profound implications for metabolic health. This review aims to summarize the roles of key Rho GTPases, RhoA, RAC1, and cell division cycle 42 (CDC42) in adipocyte differentiation, insulin signaling, and lipid droplet dynamics. Relevant research articles were retrieved via searches of available public databases, such as PubMed, and were reviewed here. For adipocyte differentiation, RhoA predominantly acts as a negative regulator during the early commitment phase, whereas RAC1 and CDC42 typically promote differentiation. Furthermore, Rho GTPases are integral to insulin signaling pathways, where their dysregulation can contribute to insulin resistance. The role of Rho GTPases in lipid droplet dynamics appears to be involved in the stabilization of lipid droplets through the regulation of the formation of actin stress fibers, whereas RAC1 facilitates droplet mobilization and degradation. The therapeutic potential of Rho GTPase pharmacological inhibitors and their efficacies in reducing lipid accumulation and improving insulin sensitivity in preclinical models are discussed. Nevertheless, challenges such as the specificity of these inhibitors and the complexity of the underlying mechanisms still remain. The development of highly specific modulators and full elucidation of signaling cascades are imperative to fully exploit Rho GTPases as promising therapeutic targets for combating obesity, type 2 diabetes, and related metabolic disorders.