Mobilization efficiency is critically regulated by fat via marrow PPARd

Tomohide Suzuki, Shinichi Ishii, Masakazu Shinohara, Yuko Kawano, Kanako Wakahashi, Hiroki Kawano, Akiko Sada, Kentaro Minagawa, Michito Hamada, Satoru Takahashi, Tomoyuki Furuyashiki, Nguan Soon Tan, Toshimitsu Matsui, Yoshio Katayama

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 d (PPARd), 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 PPARd might inhibit mobilization. A PPARd agonist inhibited mobilization in mice fed a normal diet and enhanced mobilization by a fat-free diet. Mice treated with a PPARd antagonist and chimeric mice with PPARd+/- bone marrow showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that bone marrow PPARd 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 ω3-polyunsaturated fatty acids such as eicosapentaenoic acid. Eicosapentaenoic acid induced the upregulation of genes downstream of PPARd, such as Cpt1α 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, PPARd signaling in mature/immature bone marrow neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.

Original languageEnglish (US)
Pages (from-to)1671-1683
Number of pages13
JournalHaematologica
Volume106
Issue number6
DOIs
StatePublished - Jun 2021

All Science Journal Classification (ASJC) codes

  • Hematology

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