Activation of NF-κB Signaling by a High-Fat and High-Sugar Diet Enhances Macrophage Polarization and Aggravates Postoperative Pain and Inflammatory Responses.

Objective: To investigate how a high-fat, high-sugar (HFHS) diet influences postoperative pain and inflammation, and to explore the role of NF-κB signaling and macrophage polarization.

Methods: Male Sprague Dawley rats were divided into five groups: normal diet (ND), HFHS, ND + surgery (ND + S), HFHS + surgery (HFHS + S), and HFHS + surgery + NF-κB inhibitor (HFHS + S + B). After eight weeks of diet, laparotomy was performed. Pain behavior was assessed using the Rat Grimace Scale. DRG and blood samples were collected for Western blotting, ELISA, flow cytometry, and immunofluorescence.

Results: HFHS combined with surgery significantly activated NF-κB signaling, shown by increased p65/IκBα phosphorylation and COX-2 upregulation. NF-κB inhibition reversed these effects and reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1) and pain scores. HFHS and surgery also increased M1 and decreased M2 macrophages; these changes were reversed by NF-κB blockade. Western blotting confirmed upregulation of iNOS and IL-6 and downregulation of Arg-1 and IL-10 under HFHS conditions.

Conclusion: An HFHS diet exacerbates postoperative pain and inflammation via NF-κB activation and M1 macrophage polarization. Inhibiting NF-κB may mitigate diet-induced sensitization.