Abstract
Despite recent in vivo data demonstrating that high-fat diet (HFD)-induced obesity leads to major perturbations in murine hematopoietic stem cells (HSC), the direct role of a HFD is not yet completely understood. Here, we investigate the direct impact of a short-term HFD on HSC and hematopoiesis in C57BL/6J mice compared with standard diet-fed mice. We detect a loss of half of the most primitive HSC in the bone marrow (BM) cells of HFD-fed mice, which exhibit lower hematopoietic reconstitution potential after transplantation. Impaired maintenance of HSC is due to reduced dormancy after HFD feeding. We discover that a HFD disrupts the TGF-β receptor within lipid rafts, associated to impaired Smad2/3-dependent TGF-β signaling, as the main molecular mechanism of action. Finally, injecting HFD-fed mice with recombinant TGF-β1 avoids the loss of HSC and alteration of the BM’s ability to recover, underscoring the fact that a HFD affects TGF-β signaling on HSC.
Highlights
Despite recent in vivo data demonstrating that high-fat diet (HFD)-induced obesity leads to major perturbations in murine hematopoietic stem cells (HSC), the direct role of a HFD is not yet completely understood
In this study on mice, we found that ingesting a HFD for as little as 4 weeks can affect the organization of Lipid rafts (LR) on the surface of HSC, which in turn disturbs the LR/TGF-β signaling
We observed that HSC had high level of LR, but the levels decreased in more mature progenitor cells
Summary
Despite recent in vivo data demonstrating that high-fat diet (HFD)-induced obesity leads to major perturbations in murine hematopoietic stem cells (HSC), the direct role of a HFD is not yet completely understood. Reside at the top of the hematopoietic hierarchy and have capacities of self-renewal and differentiation which are essential for the lifelong sustenance of the stem cell pool and the production of all types of blood cells, respectively[1,2]. Both of these abilities are finely regulated by both cell-intrinsic and cellextrinsic mechanisms involving cytokines, transcription factors and cell–cell contacts[3], as well as epigenetic regulation[4]. As platforms for membrane trafficking and signal transduction, LR are master regulators of cytokine function, cell cycle activity and are involved in the retention/dormancy of HSC in bone marrow (BM)[20,21,22]
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