Regulation of hormone-sensitive lipase in neurons

Projektinformationen

RELINEU

ID Finanzhilfevereinbarung: 101148076

DOI

10.3030/101148076

Projekt abgeschlossen

EK-Unterschriftsdatum 26 März 2024

Startdatum 1 Mai 2024

Enddatum 30 April 2026

Finanziert unter

• Marie Skłodowska-Curie Actions (MSCA)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 222 727,68

Koordiniert durch

LUNDS UNIVERSITET
Sweden

Periodic Reporting for period 1 - RELINEU (Regulation of hormone-sensitive lipase in neurons)

Berichtszeitraum: 2024-05-01 bis 2026-04-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Lipids are essential components of the brain. They not only provide structural support to neurons and myelin but also regulate key processes such as neuronal communication, blood flow, inflammation, and energy metabolism. Alterations in brain lipid signalling are increasingly associated with ageing and neurological disorders, yet many of the molecular mechanisms controlling these pathways remain poorly understood.
This project focused on hormone-sensitive lipase (HSL), an enzyme best known for its role in fat metabolism in peripheral tissues such as adipose tissue. Importantly, HSL is also present in the brain, including in neurons and synapses, where it may participate in the production of bioactive lipids involved in neuronal signalling. Unlike other lipases, HSL is uniquely regulated through phosphorylation by the cAMP-dependent protein kinase pathway, linking its activity to hormone and neurotransmitter signalling. This makes HSL a promising candidate for connecting neuronal activity with lipid-mediated regulation of brain physiology.
Previous work showed memory impairment in mice lacking HSL, particularly during ageing or under metabolic stress such as high-fat feeding, which suggests that HSL plays an important role in maintaining normal brain function and cognitive health. However, the mechanisms regulating HSL activity in neurons, as well as the physiological consequences of its activation at the cellular level, remained largely unknown.
The overall objective of this project was therefore to investigate how HSL is regulated in neurons and to determine how its activity influences neuronal function. Using human-derived neuronal cell lines and primary mouse neurons, the project combined cellular and molecular approaches to study both the activation mechanisms of HSL and its downstream effects on neuronal physiology.
By improving our understanding of how lipid metabolism is regulated in the brain, this research is expected to contribute to the identification of novel mechanisms involved in brain ageing and neurological dysfunction. In the longer term, the findings may support the development of new strategies targeting lipid signalling pathways to preserve cognitive function and brain health under ageing and metabolic stress conditions

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The project investigated the regulation and function of hormone-sensitive lipase (HSL) in neurons using a combination of cellular and neurobiological approaches.
A first objective was to establish suitable experimental models to study HSL activity in neuronal systems. Several neuronal cell lines were evaluated, leading to the identification of a suitable cell model robustly and reproducibly expressing HSL. Experimental pipelines were developed and optimised to monitor HSL activation, using phosphorylation-based assays as a reliable readout. Using these optimised systems, the project identified key signalling pathways regulating HSL activity in neurons. Activation of the cAMP/protein kinase A (PKA) pathway resulted in a consistent increase in HSL activation. This effect was observed following treatment with forskolin, β-adrenergic agonists, and neuronal depolarisation stimuli. These findings were validated across cell lines and primary mouse neurons, demonstrating that the regulation of HSL is conserved across neuronal models.
In parallel, primary neuronal cultures derived from wild-type and HSL knockout mice were successfully established and used to investigate the neurophysiological role of HSL. These models enabled the assessment of multiple aspects of neuronal function, including neuronal morphology, activity, and selected metabolic parameters. In particular, the HSL emerged as a critical regulator of lipid storage upon increased fatty acid overload.
Together, these results provide the first experimental evidence of how HSL activity is regulated in neurons and support its role as a mediator linking extracellular signals to neuronal lipid metabolism. The project also established robust and reproducible experimental platforms that enable further investigation of HSL function in the brain.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

This project provides novel insights into the regulation of hormone-sensitive lipase (HSL) in the brain, addressing an important gap in our understanding of neuronal lipid metabolism. While HSL is well characterised in peripheral tissues, its role and regulation in neurons have remained largely unexplored.
A key advancement of this work is the identification of specific signalling pathways that regulate HSL activity in neuronal cells. The results demonstrate that HSL activation is controlled by the cAMP/protein kinase A (PKA) pathway in response to defined extracellular stimuli, including β-adrenergic signalling and neuronal depolarisation. This establishes, a direct mechanistic link between neuronal activity-related signalling and HSL activation.
Importantly, the findings also indicate that HSL regulation in neurons is selective, as other signalling pathways did not significantly influence its activation. This specificity suggests that HSL may act as a finely tuned mediator linking extracellular cues to intracellular lipid metabolism.
Beyond the identification of regulatory mechanisms, the project has established experimental platforms to study HSL function in neuronal systems, including human neuronal models and primary neurons. These tools represent an important step forward for the field, enabling future investigations into the role of lipid metabolism in brain function.
Collectively, these results advance the current state of the art by positioning HSL as a potential molecular link between extracellular signalling, neuronal activity, and the regulation of bioactive lipid pathways in the brain. Given the importance of lipid signalling in processes such as neurovascular coupling, energy metabolism, and neuron–glia communication, this work opens new avenues for understanding how metabolic and signalling pathways intersect in the central nervous system.
The project lays the groundwork for future research aimed at defining the downstream functional consequences of HSL activation in neurons and its role in brain physiology and pathology. Further studies will be required to characterise how HSL-dependent lipid pathways influence neuronal function at the systems level and whether they contribute to cognitive decline associated with ageing and metabolic disorders.
To ensure further uptake and impact, key needs include:
• deeper functional validation of HSL-dependent pathways in vivo;
• integration with lipidomic and metabolic profiling approaches;
• exploration of HSL as a potential therapeutic target in neurological and metabolic diseases.
In the longer term, a better understanding of HSL function in the brain may contribute to the development of strategies targeting lipid signalling pathways to preserve cognitive function and brain health.