High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptor γ

The aim of the present study was to investigate the influence of a high-fat diet (HFD) on hematopoietic system recovery under stress condition caused by 5-fluorouracil (5-Fu) and to evaluate the alleviating benefit of proliferator-activated receptor γ (PPAR-γ) inhibition on aggravation of 5-Fu-induced toxicity under HFD. Survival rates of HFD or normal diet (ND) mice were monitored after 5-Fu injection. Hematopoietic stem cells (HSCs) and the progenitor cells in bone marrow were detected at various time points after 5-Fu administration by flow cytometry. Genes expressed in stem cell and platelet proliferation was tested by reverse transcription polymerase chain reaction. The blood cell profile and coagulation function were determined with an ADVIA 120 hematology system and rotational thromboelastometry, respectively. None of HFD mice remained alive after 5-Fu injection, whereas 87.4% of ND mice survived. HFD accelerated 5-Fu-induced myelosuppression and cytopenia in the circulation, reflected by the worse recovery of HSCs and myeloid progenitor cells. In HFD mice, the number of platelets significantly decreased, and the Vcam-1/Vla-4 signal pathway was downregulated in bone marrow. Meanwhile, mice receiving HFD exhibited dysfunction of blood coagulation with increased clotting formation time. However, pretreatment of HFD mice with bisphenol A diglycidyl ether (BADGE), the PPAR-γ antagonist, reversed the acute lethal toxicity and bone marrow suppression of 5-Fu and accelerated the recovery of HSCs and platelets. In the light of these results, HFD could exacerbate 5-Fu-induced bone marrow toxicity and cytopenia. BADGE treatment offers a potential strategy to alleviate the aggravated hematopoiesis under an HFD.