Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

Abstract

During infection, cellular resources are allocated toward synthesis and secretion of effector proteins that neutralize and kill invading pathogens. In Drosophila, antimicrobial peptides (AMPs) are produced in the fat body, an organ that also serves as a major nutrient storage depot.Here we asked how the innate immune response activated by fat body Toll signaling alters lipid metabolism as a model for understanding how the cellular and energetic demands of the immune response are met. We find that genetic activation of fat body Toll signaling leads to a tissueautonomous reduction in triglyceride storage that is paralleled by decreased transcript levels of Lipin and midway, enzymes that carry out the final steps of triglyceride synthesis. In contrast, Kennedy pathway enzymes that synthesize phospholipids and their products, phosphatidylcholine and phosphatidylethanolamine, are induced in fat bodies with active Toll signaling. Induction of these enzymes depends on the unfolded protein response mediator Xbp1, and examination of endoplasmic reticulum (ER) morphology by transmission electron microscopy revealed significantly expanded ER in fat body cells with active Toll signaling.Together these results indicate that Toll signaling induces a metabolic switch from triglyceride storage to phospholipid synthesis and ER expansion; this occurs in response to AMP production and may sustain AMP synthesis and secretion during infection. Better understanding of how this anabolic switch in lipid metabolism is induced, as well as the long-term consequences of reduced triglyceride storage at the expense of phospholipid synthesis, should yield insight into metabolic diseases that stem from chronic inflammation.

Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

“…Lipin transcript levels decrease by 50% when an immune response is stimulated by expression of a constitutively active Toll receptor in the fat body. This decrease is associated with a reduction in triglyceride storage (66). Together, these observations further strengthen previously observed links between lipid metabolism and the immune response in Drosophila (67).…”

Reassessment of Pioglitazone for Alzheimer’s Disease

“…Gene expression analysis of human AD subjects and mouse AD models reveal increasing reliance on lipid metabolism with disease progression as glucose consumption decreased ( Yao et al, 2011 ; Demarest et al, 2020 ). Alternatively, the stored triglycerides may be used to synthesize membranes in support of phagocytosis, or in response to stress ( Martínez et al, 2020 ). Finally, intracellular lipid droplets may be centers for coordinating glial-based responses to infectious agents, by attracting pathogenic microbes and acting as reservoirs for antimicrobial peptides and nucleation sites for other immune proteins, including RSAD2 ( Bosch et al, 2020 ).…”

An Integrated Transcriptomics and Lipidomics Analysis Reveals That Ergosterol Is Required for Host Defense Against Bacterial Infection in Drosophila

“…Innate immune system is critical for host survival, yet energetically expensive for a full protection during immune challenges, requiring proper re-distribution of energy (6). Upon pathogen invasion, Drosophila hemocytes sense and initiate a metabolic switch to aerobic glycolysis for boosting the immune response (7,8). Furthermore, the activation of the Imd pathway and/or the Toll pathway in fat body disrupts insulin signaling, results in decreased triglyceride storage and impaired animal growth (9)(10)(11).…”