Biology subjects

Boisjoly, F.

Publications and source records attributed to Boisjoly, F..

3 recordsLinked to original sources

bioRxiv2025

DGAT1-dependent lipid droplet synthesis in microglia attenuates neuroinflammatory responses to lipopolysaccharides.

Lipid droplets (LD) are dynamic storage organelles for triglycerides (TG). LD act as a hub that modulates the availability of fatty acids to sustain metabolic needs and the generation of fatty-acid derived signals. Recent evidence demonstrates that LD metabolism regulates immune responses including in microglia, the resident immune cells of the central nervous system. We have previously shown that blocking LD lipolysis in microglia reduces acute pro-inflammatory responses to lipopolysaccharide (LPS) including cytokine and prostanoid synthesis. Here, we investigated the role of diacylglycerol O-acyltransferase 1 (DGAT1), a key enzyme catalyzing the final step of TG synthesis, in microglial LD biogenesis and inflammatory responses induced by LPS. We found that treatment with LPS downregulates specific enzymes in the TG synthesis pathway in primary microglia, including GPAT1, AGPAT3, AGPAT5, and DGAT1, while upregulating TMEM68, a non-canonical TG synthesizing enzyme. Pharmacological inhibition of DGAT1 significantly reduced LD formation in both oleate- and LPS-stimulated conditions, indicating that DGAT1 is essential for inflammation-induced LD synthesis. Moreover, DGAT1 inhibition selectively decreased expression of pro-inflammatory cytokines TNF- and IL-1{beta}, without affecting IL-6, CCL2, or the anti-inflammatory cytokine TGF-{beta}. These findings show, that DGAT1-dependent LD formation acts as an important modulator of microglial inflammatory signaling.

neuroscience↗

bioRxiv2025

Immunometabolic state modulation of sequential decision making in patch-foraging mice

Animals have evolved sophisticated behavioural and metabolic adaptations to respond to threats to homeostasis, including resource scarcity and infectious pathogens. Energy deficits associated with lack of food availability and sickness-associated anorexia elicit distinctive hypometabolic states, however how such states are integrated with higher-order cognition is largely unknown. Patch-foraging paradigms have proven useful for deciphering evolutionarily conserved and ethologically grounded insights into cost-benefit decision-making as animals continually deliberate between exploiting and exploring their environment. We developed and extensively validated a touchscreen-based patch-foraging task for mice in which food reward dynamically varied across trials, in a dataset comprising over 111,000 sequential decisions from 35 adult male mice. Contrary to predictions that emphasize the impact of inflammation to blunt effortful reward-driven behaviour, our results demonstrate that systemic lipopolysaccharides-induced inflammation promotes hyper-exploitation by attenuating exploratory choice behaviour in animals interacting with complex food environments. Such behaviour can be seen as a bias towards immediate outcomes, with impulsivity as a feature affecting the weighting of temporal factors. Given the ubiquity of systemic inflammation in numerous infectious, metabolic and psychiatric disorders featuring dysfunctional value- and cost-sensitive behaviour, these results provide insight into how immunometabolic states are linked to altered decision-making.

neuroscience↗

bioRxiv2023

Microglial adipose triglyceride lipase regulates neuroinflammatory and behavioural responses to LPS

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.

neuroscience↗