Abstract

Adult neural stem and progenitor cells (NSPCs) show high levels of fatty acid synthase (Fasn)-dependent de novo lipogenesis, a process that is controlled by Spot14 to regulate the rate of proliferation; this indicates a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation. The mechanisms by which the cellular metabolic program controls the proliferative activity of endogenous stem cells, such as the neural stem and progenitor cells (NSPCs) in the mammalian brain, are unknown. Sebastian Jessberger and colleagues now report a connection between de novo lipid biosynthesis and NSPC proliferation in the brain. Specifically, they find that fatty acid synthase is highly active during adult neurogenesis in the hippocampus. The Spot14 gene is highly expressed in proliferating NSPCs, thereby limiting the availability of the fatty acid synthase substrate malonyl-CoA and suppressing lipidogenesis and neural differentiation. Mechanisms controlling the proliferative activity of neural stem and progenitor cells (NSPCs) have a pivotal role to ensure life-long neurogenesis in the mammalian brain1. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (Fasn), the key enzyme of de novo lipogenesis2, is highly active in adult NSPCs and that conditional deletion of Fasn in mouse NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene previously implicated in lipid metabolism3,4,5, that we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA6, which is an essential substrate for Fasn to fuel lipogenesis. Thus, we identify here a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation.