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Browsing by Subject "Beige adipogenesis"
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Item Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis(Frontiers Media, 2022-06-13) Wei, Lei; Shi, Jianjian; Pediatrics, School of MedicineObesity 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.Item ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice(Wiley, 2020-01) Wei, Lei; Surma, Michelle; Yang, Yang; Tersey, Sarah; Shi, Jianjian; Pediatrics, School of MedicineThe RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase-dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high-fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal-vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro-beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity-mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age-related and diet-induced fat mass gain and insulin resistance.