Our diet and microbiome have a big influence on our bodies, but how these directly influence tissue stem cell function remains poorly understood. In this paper, we investigated how molecular pathways involved in blood stem cell maintenance were influenced by a high-fat diet. We identified a gene called Spred1 as playing an important role in stem cell activity and as a tumor suppressor in the context of a high-fat diet. These findings are helping us to understand the links between metabolism and stem cell activity.