Neutrophil behavior during the metabolic adaptations to short term high fat feeding

Background and Aims: Neutrophils participate to the chronic metabolic consequences of High Fat Diet (HFD). Nevertheless, neutrophils are characterized by short half-life which is determined by a fine tuning in expression and function of CXCR4, which dictates the egress from the bone marrow (BM), and CXCR2, which facilitates their mobilization from BM and the patrolling activity in the periphery. In the quest to study the behavior of the neutrophil with the short-term consequences of HFD feeding, we studied whether the metabolic adaptations affect blood neutrophil count and the membrane expression of their indirect markers of function. Methods: To assess the gluco-metabolic impact of a short-term HFD feeding, indirect calorimetry and plasma glucose dosage were performed on mice previously fed a HFD (60% Kcal from fat) for seven days, followed by immunophenotyping of blood over 24 hours. To test whether changes in circulating neutrophil count during short-term HFD feeding were related to a differential egress from the BM, we repeated the same experimental design in mice harboring a conditional deletion of CXCR4 (CXCR4fl/flMrp8Cre+). Results: Short-term HFD feeding was sufficient to induce a profound metabolic impact (e.g. reduced respiratory exchange ratio, increased energy expenditure, and insulin levels), and to induce an increase of circulating neutrophils (p=0,052), without impacting other leukocytic fractions over 24 hours, compared to chow diet feeding mice (20% Kcal from fat). HFD feeding significantly altered the expression pattern of multiple membrane markers of neutrophil function (CD11b, CD62L, CXCR2) over 24 hours, driving neutrophils toward a phenotype featuring increased migration and activation. Finally, the CXCR4fl/flMrp8Cre+ mice, which present significantly higher circulating neutrophilia, showed lower insulin sensitivity upon HFD compared to WT. Conclusions: We suggest that the metabolic adaptations induced by a short-term exposure to HFD affect neutrophil behavior, surmising it as an appealing target for cardio-metabolic diseases.