Pharmacological inhibition of casein kinase II attenuates metaflammation in a murine model of diet‑induced metabolic dysfunction.

Abstract

Kinases are activators of well‑known inflammatory cascades implicated in metabolic disorders, and abnormal activation of casein kinase II (CK2) is associated with several inflammatory disorders. However, thus far, its role in the low‑grade chronic inflammatory response known as 'metaflammation', which is a hallmark of obesity and type 2 diabetes, has not yet been elucidated. The present study aimed to evaluate the role of CK2 in diet‑induced metaflammation and the effects of the CK2 inhibitor 4,5,6,7‑tetrabromobenzotriazole (TBB) on a murine model fed a high‑fat‑high‑sugar (HFHS) diet. C57BL/6JOlaHsd mice were fed a standard diet (n=12) or HFHS diet (n=24) for 12 weeks. A subgroup of the HFHS group received TBB (2.5 mg/kg/day, orally, n=12) for the last 8 weeks. Subsequently, plasma and liver samples were harvested for ex vivo biomolecular analyses (immunohistochemistry, western blotting, multiplex assay to determine the plasma levels of pro‑inflammatory cytokines, reverse transcription‑quantitative PCR and enzymatic assays) Statistical significance was determined using one‑way ANOVA with post‑hoc analysis (P<0.05). The results revealed that HFHS feeding induced glucose and lipid intolerance, elevated circulating pro‑inflammatory cytokines and increased hepatic neutrophil infiltration. By contrast, TBB treatment improved glucose and lipid homeostasis, and reduced systemic inflammation without altering body weight. Notably, TBB attenuated hepatic inflammation, reduced neutrophil recruitment and suppressed HFHS‑induced CK2α hyperactivation. This was accompanied by modulation of key inflammatory pathways, including NFκB/nucleotide‑binding domain, leucine‑rich‑containing family, pyrin domain‑containing‑3 and AMPK signaling. In conclusion, the present study demonstrated the beneficial effects of pharmacological inhibition of CK2 in a murine model of diet‑induced metabolic dysfunction, identifying CK2 as a potential target for dampening metaflammation. The efficacy of TBB in relieving hepatic inflammation was mainly due to the interference with selective inflammatory pathways.