Drosophila Snazarus Regulates a Lipid Droplet Population at Plasma Membrane-Droplet Contacts in Adipocytes

Adipocytes store nutrients as lipid droplets (LDs), but how they organize their LD stores to balance lipid uptake, storage, and mobilization remains poorly understood. Here, using Drosophila fat body (FB) adipocytes, we characterize spatially distinct LD populations that are maintained by different lipid pools. We identify peripheral LDs (pLDs) that make close contact with the plasma membrane (PM) and are maintained by lipophorin-dependent lipid trafficking. pLDs are distinct from larger cytoplasmic medial LDs (mLDs), which are maintained by FASN1-dependent de novo lipogenesis. We find that sorting nexin CG1514 or Snazarus (Snz) associates with pLDs and regulates LD homeostasis at ER-PM contact sites. Loss of SNZ perturbs pLD organization, whereas Snz over-expression drives LD expansion, triacylglyceride production, starvation resistance, and lifespan extension through a DESAT1-dependent pathway. We propose that Drosophila adipocytes maintain spatially distinct LD populations and identify Snz as a regulator of LD organization and inter-organelle crosstalk. [Display omitted] •Drosophila adipocytes have distinct LD pools including peripheral LDs (pLDs)•pLDs contact the plasma membrane and change during fasting and high-nutrient diet•Snazarus (Snz) localizes to the cell periphery at ER-PM contacts and binds to LDs•Snz over-expression promotes TAG storage, starvation resistance, and longer lifespan Adipocytes store fat in lipid droplets (LDs), but how this is organized remains unclear. Ugrankar et al. show that Drosophila adipocytes organize their LDs into spatially and functionally distinct sub-populations. Snazarus localizes to ER-PM contacts and binds to peripheral LDs to regulate fat storage, and influences fly health and lifespan.