The Exchangeable Apolipoprotein Nplp2 Sustains Lipid Flow and Heat Acclimation in Drosophila

In ectotherms, increased ambient temperature requires the organism to consume substantial amounts of energy to sustain a higher metabolic rate, prevent cellular damage, and respond to heat stress. Here, we identify a heat-inducible apolipoprotein required for thermal acclimation in Drosophila. Neuropeptide-like precursor 2 (Nplp2) is an abundant hemolymphatic protein thought to be a neuropeptide. In contrast, we show that Nplp2 contributes to lipid transport, functioning as an exchangeable apolipoprotein. More precisely, Nplp2-deficient flies accumulate lipids in their gut, have reduced fat stores, and display a dyslipoproteinemia, showing that Nplp2 is required for dietary lipid assimilation. Importantly, Nplp2 is induced upon thermal stress and contributes to survival upon heat stress. We propose that Nplp2 associates with lipoprotein particles under homeostatic and high energy-demand conditions to optimize fat transport and storage. Our study also shows that modulation of the lipid uptake and transport machinery is part of an integrated cytoprotective response. [Display omitted] •We identified Nplp2, an exchangeable apolipoprotein in Drosophila•Nplp2 maximizes Lipophorin lipid loading capacity•Nplp2 controls dietary lipid extraction and optimal fat storage•Nplp2 fuels the stress response with dietary lipids and promotes heat acclimation Rommelaere et al. identify a small exchangeable apolipoprotein in Drosophila that facilitates dietary lipid extraction and fat storage. Nplp2 sustains lipid flow to fuel the heat stress response, promoting insect survival at elevated temperatures. Optimization of lipid transport during stress via dedicated lipoproteins likely applies to other species including vertebrates.