Mobilization efficiency is critically regulated by fat via marrow PPARδ

The efficiency of mobilization of hematopoietic stem/progenitor cells from bone marrow into the circulation by granulocyte colony-stimulating factor (G-CSF) is extremely varied in humans and mice and a mechanistic explanation for poor mobilizers is lacking. A mechanism of regulating mobilization efficiency by dietary fat was assessed in mice. Compared to a normal diet, a fat-free diet for 2 weeks greatly increased mobilization. The bone marrow mRNA level of peroxisome proliferator-activated receptor delta (PPAR delta), a receptor for lipid mediators, was markedly upregulated by G-CSF in mice fed a normal diet and displayed a strong positive correlation with widely varied mobilization efficiency. It was hypothesized that the bone marrow fat ligand for PPAR delta might inhibit mobilization. A PPAR delta agonist inhibited mobilization in mice fed a normal diet and enhanced mobilization by a fat-free diet. Mice treated with a PPAR delta antagonist and chimeric mice with PPAR delta(+/-) bone marrow showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that bone marrow PPAR delta expression was enhanced by G-CSF mainly in mature/immature neutrophils. Analysis of bone marrow lipid mediators revealed that G-CSF treatment and a fat-free diet resulted in exhaustion of omega 3-polyunsaturated fatty acids such as eicosapentaenoic acid. Eicosapentaenoic acid induced the upregulation of genes downstream of PPAR delta, such as Cpt1 alpha and Angptl4, in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with a fat free diet in vivo. Treatment of wild-type mice with anti-Angptl4 antibody enhanced mobilization as well as bone marrow vascular permeability. Collectively, PPAR delta signaling in mature/immature bone marrow neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.