Reversing an obesogenic diet to control diet partially rescues pro-inflammatory lipid–immune memory in splenocardiac aging

Introduction: Chronic exposure to an obesogenic diet (OBD) induces systemic inflammation and disrupts lipid-immune homeostasis, but its long-term effects and potential reversibility with aging remain unclear. Aim: This study examined whether switching from an OBD to a control diet can restore lipid-immune homeostasis during aging and evaluated associated changes in myocardial infarction (MI) response, macrophage activation, and immune cell heterogeneity. Methods and Results: Male C57BL/6J mice were fed either a control or OBD diet for six months, followed by continued OBD or dietary reversal (OBD-R) for an additional four months. Cardiac function, splenic and cardiac lipid mediators, leukocyte profiles, and gene expression were assessed at baseline and post-MI. Lipopolysaccharide (LPS)-induced macrophage activation assays and single-cell RNA sequencing (scRNA-seq) of CD45+ cells were performed to characterize immune memory. Chronic OBD induced cardiac strain dysfunction, expansion of CCR2+ macrophages, elevated 12-HETE levels, and depletion of specialized pro-resolving mediators (SPMs). Dietary reversal restored SPMs, normalized certain immune parameters, and improved post-MI responses, but persistent activation of the 12-HETE-driven CCL2-CCR2/ALOX5-ALOX5AP axis maintained proinflammatory macrophage memory. scRNA-seq revealed diet-dependent transcriptional remodeling of immune populations, and LPS assays confirmed heightened inflammatory memory in macrophages after chronic OBD exposure. Conclusions: Dietary intervention can potentially resolve OBD-induced inflammation and mitigate related cardiovascular consequences during aging, with the 12-HETE-induced CCL2-CCR2/ALOX5-ALOX5AP axis playing a critical role in shaping macrophage phenotype and sustaining inflamed immune memory.