STIM2β is a Ca2+ signaling modulator for the regulation of mitotic clonal expansion and PPARG2 transcription in adipogenesis

Su Ji Jeong; Bo-Woong Sim; Sun-Uk Kim; Chan Young Park

doi:10.1111/febs.70118

STIM2β is a Ca²⁺ signaling modulator for the regulation of mitotic clonal expansion and PPARG2 transcription in adipogenesis

FEBS J. 2025 May 9. doi: 10.1111/febs.70118. Online ahead of print.

Authors

Su Ji Jeong¹, Bo-Woong Sim², Sun-Uk Kim², Chan Young Park³

Affiliations

¹ Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
² Futuristic Animal Resource & Research Center (FARRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Korea.
³ Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Korea.

PMID: 40344531
DOI: 10.1111/febs.70118

Abstract

Intracellular Ca²⁺ is crucial in the regulation of adipocyte lipid metabolism and adipogenesis. In this study, we aimed to investigate the regulation mechanism of intracellular Ca²⁺ levels ([Ca²⁺]_i) during adipocyte differentiation. We found that the expression of stromal interaction molecule 2 beta (STIM2β), which is the inhibitor of store-operated Ca²⁺ entry (SOCE), is upregulated throughout the differentiation process. Evaluation of [Ca²⁺]_i in 3 T3-L1 and primary stromal vascular fraction (SVF) cells revealed that the basal Ca²⁺ level is downregulated after differentiation. Knockout (KO) of STIM2β in 3T3-L1 and primary SVF cells showed increased [Ca²⁺]_i, indicating the involvement of STIM2β in the regulation of [Ca²⁺]_i during adipogenesis. We further evaluated the function of STIM2β-mediated [Ca²⁺]_i in early and terminal differentiation of adipogenesis. Analysis of cell proliferation rate during mitotic clonal expansion (MCE) in wild-type and STIM2β KO 3T3-L1 cell lines revealed that a larger population of KO cells underwent G1 arrest, suggesting that reduced [Ca²⁺]_i by STIM2β induces MCE. Additionally, ablation of STIM2β increased differentiation efficiency, with more lipid accumulation and rapid transcriptional activation of adipogenic genes, especially proliferator-activator receptor γ2 (PPARG2). We found that PPARG2 transcription is regulated by store-operated calcium entry (SOCE) downstream transcription factors, confirming that increased [Ca²⁺]_i by STIM2β ablation promotes PPARG2 transcription during adipogenesis. Additionally, STIM2β KO mice showed hypertrophic adipose tissue development. Our data suggest that STIM2β-mediated [Ca²⁺]_i plays a pivotal role in the regulation of mitotic clonal expansion and PPARG2 gene activation and provides evidence that MCE is not a prerequisite process for terminal differentiation during adipogenesis.

Keywords: PPARγ2; STIM2β; adipogenesis; cell cycle regulation; intracellular Ca2+.

Abstract

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