Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

Robb, J. L.; Machuca-Parra, A. I.; Boisjoly, F.; Coursan, A.; Manceau, R.; Majeur, D.; Rodaros, D.; Bouyakdan, K.; Greffard, K.; Bilodeau, J.-F.; Forest, A.; Daneault, C.; Ruiz, M.; Laurent, C.; Arbour, N.; Laye, S.; Fioramonti, X.; Madore-Delpech, C.; Fulton, S.; Alquier, T.

doi:10.1101/2023.11.30.569441

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bioRxiv · 10.1101/2023.11.30.569441

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

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Abstract

Adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral tissues. ATGL has been associated with both pro- and anti-inflammatory responses in different tissues suggesting its actions are dependent on cell type. Recent studies in microglia and macrophages suggest that lipid droplets (LD), a triglyceride storing organelle, and LD lipolysis via ATGL are important components of inflammatory responses. Here, we determined the impact of ATGL inhibition and microglia-specific ATGL loss-of-function on inflammatory and behavioural responses to acute pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines in mouse primary microglia cultures. LPS led to LD accumulation in microglia and altered the expression of lipolysis regulators. The pan-lipase inhibitor ORlistat alleviated LPS-induced expression of IL-1{beta} and IL-6. Specific inhibition of ATGL by ATGListatin had similar anti-inflammatory action on cytokines expression and secretion in both neonatal and adult microglia cultures. Second, targeted and untargeted lipidomic studies revealed that ATGL inhibition reduced LPS-induced generation of pro-inflammatory prostanoids and affected ceramide profile. Finally, the role of ATGL in neuroinflammation was assessed in a novel mouse model with inducible ATGL deletion specifically in microglia. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and reduced LPS-induced sickness behaviour. Together, our results demonstrate that pharmacological inhibition or loss of ATGL-mediated triglyceride lipolysis reduces LPS-induced inflammation to suggest that inhibition of lipolysis plays a beneficial role in neuroinflammation.

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Robb, J. L., Machuca-Parra, A. I., Boisjoly, F., Coursan, A., Manceau, R., Majeur, D., Rodaros, D., Bouyakdan, K., Greffard, K., Bilodeau, J.-F., Forest, A., Daneault, C., Ruiz, M., Laurent, C., Arbour, N., Laye, S., Fioramonti, X., Madore-Delpech, C., Fulton, S., Alquier, T.. 2023-12-01. Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS. https://doi.org/10.1101/2023.11.30.569441

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