Immunometabolic Memory in Obesity: Nutritional Drivers, Persistence, and Reversibility

Obesity reshapes immune function across adipose tissue, circulation, and hematopoietic compartments. Weight reduction improves cardiometabolic health, yet emerging evidence indicates that prior obesity can leave persistent cellular, transcriptional, and epigenetic changes. Whether nutrition can reverse this biological imprint remains uncertain. We conducted a critical narrative review informed by structured searches of PubMed/MEDLINE, the Cochrane Library, and Epistemonikos, complemented by backward and forward citation tracking. We prioritized mechanistic human studies, controlled dietary interventions, longitudinal weight-loss studies, and experiments that tested persistence after stimulus withdrawal or response to re-exposure. Evidence was interpreted according to biological compartment and study design rather than pooled statistically. Obesogenic exposures can alter innate immune metabolism, inflammasome signaling, hematopoiesis, and chromatin states. Animal studies provide the strongest evidence that these changes can persist after weight normalization and amplify responses during weight regain. Human studies show incomplete normalization of adipose immune states, persistent adipocyte programs, and durable methylation changes in T lymphocytes after weight loss. Dietary interventions can lower inflammatory tone and modify immune metabolism, microbial metabolites, and lipid mediator pathways, but no dietary pattern has been shown to erase established obesity-associated immune memory in humans. An evidence map built on a core set of 47 studies showed that experimental work dominates the induction, persistence and re-challenge domains, whereas human evidence clusters in post-weight-loss remodelling and dietary modulation; human re-challenge data were absent and no study provided a direct test of reversal in humans. Obesity-associated immunometabolic memory appears to be distributed across hematopoietic, immune, adipose, stromal, and microbial compartments. Nutrition can modulate mechanisms implicated in this persistence, but human evidence of reversal is lacking, and whether pharmacologically induced weight loss leaves a comparable imprint has not been tested. Mechanistic trials should separate energy deficit, diet composition, adiposity change, and weight-loss modality and include a weight-stable follow-up and functional re-challenge where feasible.