Impact of western diet and PCSK9 on the expression of amyotrophic lateral sclerosis predisposing genes

Background and Aims: Feeding promotes the development of immune-inflammatory pathways. While this is well described in chronic pathological conditions, it is less clear if every time we eat inflammatory pathways, unique to a specific immune cell type, are activated. Here, we sought to find surrogate indicators of a cell-specific activation that emerge in the circulation during feeding. Methods: In C57Bl/6j mice we characterized both the metabolic profile (inverse calorimetry, glycemia, insulinemia and triglyceridemia) and the blood immunophenotype (to detect cell-specific markers of leukocytes via flow-cytometry), either in prandial state (feeding a chow diet) or during two hours of refeeding ad libitum after fasting. We also investigated the enrichment of plasma proteins (by untargeted proteomics) that could represent surrogate indicators of immune cellspecific activation (by pathway clustering analysis) during refeeding. Results: Chow feeding, which maintained higher prandial glycaemia, insulinemia and triglyceridemia compared to fasting, did not induce significant change in the immunophenotype, except for a tendency towards a higher abundance of CD19+ B cells. However, during re-feeding program, where glucose and triglycerides levels increased by two-to-three-fold compared to fasting unmasked a prominent increase in the blood count of Ly6G+ neutrophils, which increased one-fold compared to fasting. Of note, the counts of other leukocytes (CD3+T, CD19+ B cells and Ly6c+ monocytes) did not change. Plasma proteomics revealed enrichment of immune pathways that connects with neutrophils activation and extra-vasation. Conclusions: Our data suggest an innate, but acute, regulation of neutrophils in response to re-feeding. Further studies are needed to elucidate the underlying mechanisms and to assess the effect of more caloric diets.