Lipids are essential for neuron development and physiology1–3. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear4. Here we show the presence and functional significance of neuronal lipid droplets (nLDs) in vivo using invertebrate and vertebrate models. We validate5 the presence of nLDs in vivo and demonstrate that triglyceride metabolism enzymes and LD-associated proteins control nLD formation through both canonical and recently discovered pathways6. Modulation of nLDs has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically in neurons that couple environmental cues with energy homeostasis. Mechanistically, nLD-derived lipids support neuron function by providing fatty acids and phospholipids to sustain mitochondrial and endoplasmic reticulum function and homeostasis. This identifies a conserved role for nLDs in coordinating lipid supply and demand in neurons, which has implications for maintenance of neuronal lipid homeostasis and function in health and disease.
