Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis

ABSTRACTLipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease. HIGHLIGHTSO_LILipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network C_LIO_LINeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis C_LIO_LILD regulation supports ER and mitochondrial function in hunger-activated neurons C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/613929v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1936e92org.highwire.dtl.DTLVardef@40478aorg.highwire.dtl.DTLVardef@18d5faorg.highwire.dtl.DTLVardef@882ee9_HPS_FORMAT_FIGEXP M_FIG C_FIG