High-fat diets promote hematopoietic stem cell expansion and exercise reduces myeloid skewing during maintenance hematopoiesis

High-fat diets (HFD) and exercise (EX) exert differential impacts on hematopoietic stem and progenitor cell (HSPC) differentiation during stress hematopoiesis, in part, through alterations in the HSPC niche. However, how HFDs and EX alter HSPC differentiation during maintenance conditions remains unknown. Therefore, we examined HSPC and niche cell concentrations during maintenance hematopoiesis following a HFD and EX training intervention. Male CBA mice (<i>n</i> = 40) underwent 8 wk of HFD or control (CON) diet consumption with the latter 4 wk involving sedentary (SED) or EX training interventions. Bone marrow cells were quantified by flow cytometry, and marrow-derived HSPCs were magnetically isolated for a colony-forming unit assay. HFD mice had higher body weight, body fat percentage, and lean body mass compared with CON mice without any effect of exercise. HFD promoted HSPC and myeloid progenitor cell expansion without impacting lymphoid progenitor cells. HSPCs derived from HFD mice displayed enhanced myeloid colony formation, which was inhibited by EX. EX reduced mesenchymal stromal cell concentrations. Together, these results suggest that during maintenance hematopoiesis, EX inhibits myeloid and mesenchymal stromal cell expansion, whereas HFD opposes these effects, which is similar to their effects during stress hematopoiesis.<b>NEW & NOTEWORTHY</b> We are the first to show that exercise inhibits myeloid progenitor cell expansion and mesenchymal stromal cell concentration with high-fat diet consumption during maintenance hematopoiesis in vivo. Further, we show that exercise prevents high-fat diet-induced hematopoietic stem and progenitor cell myeloid differentiation priming. Together, our findings show an important role for exercise in regulating the maintenance of hematopoiesis under high-fat diet conditions.