Chemerin Promotes Obesity-Accelerated Orthodontic Tooth Movement by Activating IRE1α-Dependent ER Stress in PDL Fibroblasts

OBJECTIVE: To investigate the role of obesity-associated upregulation of chemerin in orthodontic tooth movement (OTM) and the underlying mechanisms. METHODS: Chemerin expression in obesity-accelerated OTM was evaluated using both in vivo (obese mice subjected to OTM) and in vitro (human periodontal ligament [hPDL] fibroblasts exposed to compression and palmitic acid treatment) models. Single-cell RNA sequencing datasets were reanalysed to identify the primary cellular sources of Rarres2 (encoding chemerin) in the periodontium. Rarres2 was overexpressed or silenced in mice and hPDL fibroblasts to assess the role of chemerin in obesity-accelerated OTM. Potential mechanisms were further investigated through integrated bioinformatic analysis and experimental validation. RESULTS: Chemerin expression was upregulated during OTM and further elevated under obese conditions. Chemerin was predominantly localised in the mouse periodontium and highly expressed in fibroblast subpopulations. Rarres2 overexpression aggravated periodontal inflammation and promoted OTM in obese mice. Furthermore, endoplasmic reticulum (ER) stress was activated in the compressed PDL under mechanical compression and chemerin was associated with elevated ER stress. Rarres2 overexpression enhanced the IRE1α-mediated ER stress in both hPDL fibroblasts and the mouse periodontium during obesity-related OTM, while Rarres2 knockdown reduced the IRE1α-mediated ER stress. Moreover, silencing of Ire1α reversed the promotive effects of Rarres2 overexpression on ER stress. CONCLUSIONS: Chemerin aggravates periodontal inflammation and accelerates obesity-related OTM by promoting IRE1α-mediated ER stress, highlighting a potential pathway for future therapeutic exploration.