Lipocalin‐2 as a fundamental protein in type 2 diabetes and periodontitis in mice

Abstract Background Lipocalin‐2 (LCN‐2) is an osteokine that suppresses appetite, stimulates insulin secretion, regulates bone remodeling, and is induced by proinflammatory cytokines. The aim of this work was to investigate the participation of LCN‐2 in periodontitis associated with type 2 diabetes (T2D) by evaluating alveolar bone loss, glycemic control, inflammation, and femur fragility. Methods A murine model of periodontitis with T2D and elevated LCN‐2 concentration was used. Functional LCN‐2 inhibition was achieved using an anti‐LCN‐2 polyclonal antibody, and isotype immunoglobulin G was used as a control. The alveolar bone and femur were evaluated by micro‐CT. Glucose metabolism was determined. Tumor necrosis factor (TNF‐α) and receptor activator of nuclear factor kappa‐B ligand (RANKL) levels in alveolar bone lysates were quantified using ELISA, and serum cytokines were quantified using flow cytometry. A three‐point bending test was performed in the femur, and RANKL levels were measured in femur lysates using ELISA. Results Functional inhibition of LCN‐2 in T2D–periodontitis mice decreased alveolar bone loss in buccal and palatal surfaces and preserved the microarchitecture of the remaining bone, decreased TNF‐α and RANKL in alveolar bone, reduced hyperglycemia, glucose intolerance, and insulin resistance, and increased insulin production through improving the functionality of pancreatic β cells. Furthermore, this inhibition increased serum free‐glycerol levels, decreased serum interleukin (IL)‐6, increased serum IL‐4, and reduced femur fragility and RANKL expression in the femur. Conclusions LCN‐2 participates in periodontitis associated with T2D. Inhibiting its function in mice with T2D and periodontitis improves pancreatic β‐cell function, and glucose metabolism and decreases inflammatory cytokines and bone‐RANKL levels, which results in the preservation of femoral and alveolar bone microarchitecture. Plain Language Summary In this study, we explored the role of a bone protein known as lipocalin‐2 (LCN‐2) in the connection between periodontitis and type 2 diabetes (T2D). Periodontitis is a destructive gum and alveolar bone disease. LCN‐2 levels are increased in both T2D and periodontitis. Using a mouse model of T2D with periodontitis, we examined how blocking LCN‐2 function affected various aspects of these two diseases. We found that this inhibition led to significant improvements. First, it reduced alveolar bone loss and preserved bone structure by decreasing local inflammation and bone resorption. Second, it improved glucose and lipid metabolism, leading to better blood‐sugar control and decreased insulin resistance. Blocking the functions of LCN‐2 also decreased systemic inflammation throughout the body and strengthened bone integrity. Overall, our results suggest that LCN‐2 plays a crucial role in the periodontitis associated with T2D. By inhibiting LCN‐2 function, we were able to improve pancreatic function, improve glucose metabolism, reduce inflammation, and enhance bone health. Targeting LCN‐2 could be a promising strategy for the harmful effects of T2D and periodontitis.