Microglial protein kinase CK2 prevents obesity in mice potentially through NLRP3 inflammasome activation

Protein kinase CK2 plays an important role in the regulation of metabolism and obesity. However, the metabolic role of CK2 and its substrates in the brain remain largely unknown. Here, we show that microglial CK2 is required for metabolic homeostasis through ASC phosphorylation and subsequent NLRP3 inflammasome–mediated interleukin (IL)−18 maturation and release.

Mice with microglia-specific, inducible deletion of CK2 regulatory subunit β (CK2β) showed obese phenotypes with weight gain, abnormal glucose homeostasis, and decreased energy expenditure. At the molecular level, CK2 phosphorylated ASC at T154, and this phosphorylation was essential for ASC aggregation and NLRP3 inflammasome activation. Microglial deletion of CK2β decreased central production of IL-18, mirroring the obese phenotypes of mice lacking IL-18 signaling.

Our results suggest that the microglial CK2–ASC–NLRP3 axis underlies the central regulation of metabolic homeostasis and prevents obesity through processing and secretion of IL-18. Nevertheless, a gap remains between these molecular mechanistic findings and the observed in vivo behavioral and metabolic phenotypes, highlighting the need for future systems-level analyses to fully delineate the broader substrate landscape of CK2 and to integrate the functional outcomes of CK2 deficiency in microglia with in vivo phenotypes. Bongki Cho (DGIST) for providing hASC cDNA and the hASC–GFP plasmid DNA.

We also thank Professor Won-Ha Lee (Kyungpook National University, Republic of Korea) for supplying THP-1 cells. This work was supported by the Korea Health Industry Development Institute (RS-2024-00439579 to S.-W.Y.) and National Research Foundation of Korea (RS-2023-NR076677 to E.-K.K.). Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea Ji-Won Lee, Nayoun Kim, Seolsong Kim, Seokjae Park, Hyeri Nam, Younghwan Lee, Seohyeon Hwang, Yeim Lee, Sehee Ha, Wonkeon Koo, Eun-Kyoung Kim & Seong-Woon Yu Neurometabolomics Research Center, DGIST, Daegu, Republic of Korea Correspondence to Eun-Kyoung Kim or Seong-Woon Yu.

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