The dual targeting effects of KD025 on casein kinase 2 and ROCK2 in a mouse model of diet-induced obesity

KD025(belumosudil), a selective ROCK2 inhibitor, exhibits unique anti-adipogenic activity through inhibition of casein kinase 2 (CK2). This study investigated the dual inhibitory effects of KD025 on metabolism in a diet-induced obese model. C57BL/6 mice on a high fat diet (HFD) were treated with KD025 for 4 weeks, while fasudil (a pan-ROCK inhibitor) and CX-4945 (a CK2-specific inhibitor) served as comparison treatments. KD025 significantly reduced body weight gain without affecting food intake, serum insulin, or fasting blood glucose levels. In contrast, while both CX-4945 and fasudil treatments showed a trend toward weight reduction, these results were not statistically significant. KD025 improved lipid metabolism by significantly lowering LDL cholesterol and triglyceride, although it slightly impaired glucose metabolism, as observed in insulin and glucose tolerance tests. Weight reduction in the KD025- and CX-4945-treated groups was attributed to decreased adipose tissue mass, particularly in inguinal (ingWAT) and epididymal (epiWAT) fat depots. Hematoxylin and eosin (H&E) staining confirmed smaller adipocyte size in these groups. KD025 had no significant effect on serum levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), or monocyte chemoattractant protein-1 (MCP-1) with varied inflammatory responses. Furthermore, KD025 and CX-4945 upregulated adipogenic and browning markers, such as Cebpa, Cidea, and Pparg in the epiWAT, though without significant UCP1 expression. Overall, KD025 effectively reduced weight gain in HFD-fed mice through dual inhibition of CK2 and ROCK2, highlighting its potential as a therapeutic agent for obesity-related conditions.