Romane Manceau, Celena M. Cherian, Danie Majeur, Colin J. Miller, Jasper D. Fisher, Frédérick Boisjoly, J. Beatrice Liston, Jennifer A. Bako, Lianna W. Wat, Charlotte F. Chao, Audrey Labarre, Serena Hollman, S. Prakash, Sébastien Audet, Lewis R Depaauw-Holt, Benjamin A. Rogers, Anthony Bosson, Puja Biswas, Yi Han Xia, Catrina A.S. Callow, Niyoosha Yoosefi, Neele Schikora, Niki Shahraki, Yi Han Xia, Alisa Hui, Jared VanderZwaag, Khalil Bouyakdan, Demetra Rodaros, Pavel Kotchetkov, Caroline Daneault, Ghazal Fallahpour, Martine Tétreault, Marie‐Ève Tremblay, Matthieu Ruiz, Baptiste Lacoste, J. Alex Parker, Ciaran Murphy‐Royal, Tao Huan, Stephanie Fulton, Elizabeth J. Rideout, Thierry Alquier
ABSTRACT Lipids 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. HIGHLIGHTS Lipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network Neuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis LD regulation supports ER and mitochondrial function in hunger-activated neurons GRAPHICAL ABSTRACT