Bone marrow adipocytes negatively regulate the hematopoietic microenvironment. In mice, adipocyte-rich regions of the skeleton, such as the tail vertebrae, have reduced hematopoietic activity compared to adipocyte-free regions like the thoracic vertebrae. Adipocytes in the bone marrow inhibit hematopoiesis by reducing the frequency and cycling capacity of hematopoietic stem cells (HSCs) and progenitors. This was demonstrated by comparing HSC and progenitor frequencies in different regions of the skeleton, showing a significant decrease in the tail vertebrae compared to the thoracic vertebrae. Additionally, in lipoatrophic "fatless" A-ZIP/F1 mice, which cannot form adipocytes, hematopoietic recovery was enhanced after irradiation, suggesting that adipocytes actively suppress hematopoiesis. Pharmacological inhibition of adipogenesis using the PPARγ inhibitor BADGE also enhanced hematopoietic recovery in wild-type mice. These findings indicate that adipocytes in the bone marrow act as negative regulators of hematopoiesis, and that reducing adipogenesis could improve hematopoietic recovery in clinical bone marrow transplantation. The study also shows that adipocytes secrete factors that impair hematopoietic proliferation, while preserving the HSC pool. The presence of adipocytes in the bone marrow is necessary to observe reduced hematopoiesis, and their removal can enhance hematopoietic engraftment. The results challenge the traditional view that adipocytes are merely passive space fillers in the marrow and suggest a novel therapeutic approach to enhance hematopoietic recovery. The study also highlights the potential role of adipocytes in myelosuppression, as seen in patients treated with PPARγ agonists like rosiglitazone. Overall, the findings demonstrate that adipocytes in the bone marrow have a suppressive effect on hematopoiesis, and that targeting adipogenesis could be a promising strategy for improving hematopoietic recovery in bone marrow transplantation.Bone marrow adipocytes negatively regulate the hematopoietic microenvironment. In mice, adipocyte-rich regions of the skeleton, such as the tail vertebrae, have reduced hematopoietic activity compared to adipocyte-free regions like the thoracic vertebrae. Adipocytes in the bone marrow inhibit hematopoiesis by reducing the frequency and cycling capacity of hematopoietic stem cells (HSCs) and progenitors. This was demonstrated by comparing HSC and progenitor frequencies in different regions of the skeleton, showing a significant decrease in the tail vertebrae compared to the thoracic vertebrae. Additionally, in lipoatrophic "fatless" A-ZIP/F1 mice, which cannot form adipocytes, hematopoietic recovery was enhanced after irradiation, suggesting that adipocytes actively suppress hematopoiesis. Pharmacological inhibition of adipogenesis using the PPARγ inhibitor BADGE also enhanced hematopoietic recovery in wild-type mice. These findings indicate that adipocytes in the bone marrow act as negative regulators of hematopoiesis, and that reducing adipogenesis could improve hematopoietic recovery in clinical bone marrow transplantation. The study also shows that adipocytes secrete factors that impair hematopoietic proliferation, while preserving the HSC pool. The presence of adipocytes in the bone marrow is necessary to observe reduced hematopoiesis, and their removal can enhance hematopoietic engraftment. The results challenge the traditional view that adipocytes are merely passive space fillers in the marrow and suggest a novel therapeutic approach to enhance hematopoietic recovery. The study also highlights the potential role of adipocytes in myelosuppression, as seen in patients treated with PPARγ agonists like rosiglitazone. Overall, the findings demonstrate that adipocytes in the bone marrow have a suppressive effect on hematopoiesis, and that targeting adipogenesis could be a promising strategy for improving hematopoietic recovery in bone marrow transplantation.