Toll signaling in the Drosophila larval fat body shifts programs of anabolic lipid metabolism and dysregulates nutrient storage
Activation of the innate immune Toll signaling pathway leads to the synthesis and secretion of antimicrobial peptides that kill invading pathogens. During an immune response, the Drosophila fat body secretes AMPs in quantities that can reach concentrations of hundreds of micromolar in hemolymph. The fat body is also a critical metabolic organ that stores dietary nutrients as glycogen and triglycerides. How these two processes – mounting an immune response and regulation of energy metabolism – are coordinated within the fat body is poorly understood. To address this question, we chronically activated Toll signaling in fat body by expressing a constitutively-active Toll receptor, Toll10b, and assessed lipid metabolism. Expression of Toll10b in the fat body leads to a tissue-autonomous decrease in triglyceride levels. Key enzymes that carry out fatty acid synthesis, such as acetyl co-A carboxylase, ATP citrate lyase, and fatty acid synthase, exhibit normal expression in animals with active Toll signaling. However, we observe 50% decreases in fat body transcript levels of both lipin, a phosphatidic acid phosphatase, and midway, the homolog of diacylglycerol acyltransferase, both of which carry out triglyceride synthesis. In contrast to effects on triglyceride storage, Toll signaling in fat body increases levels of both phosphatidylethanolamine and phosphatidylcholine in this organ. These increases are mirrored by 2.5-fold increases in transcript levels of key phospholipid synthesis enzymes, such as easily shocked, an ethanolamine kinase homolog, and Pcyt1, a phosphocholine cytidylyltransferase, in Toll10b-expressing fat bodies. Overall, chronic Toll pathway activity leads to an anabolic shift from triglyceride storage to phospholipid synthesis. A potential role for increased phospholipids may be to support endoplasmic reticulum (ER) function to sustain AMP biosynthesis required to combat infection. Indeed, transcript levels of the ER resident proteins binding immunoglobin protein and protein disulfide isomerase are increased in fat bodies expressing Toll10b, suggesting that Toll signaling drives ER expansion. Transmission electron microscopy analysis of fat bodies with chronic Toll signaling shows extensively dilated ER that takes up 40% more volume within the cell compared with control fat bodies. Conversely, there is 40% less volume of organelle-free cytoplasm in Toll10b-expressing fat bodies compared with controls. Together, these results point to a switch from triglyceride storage to phospholipid biogenesis during chronic Toll activation that may allow the fruit fly to expand ER machinery to make sizeable quantities of AMPs for fighting off invading pathogens. 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.