A study published in Nature Metabolism highlights the unexpected role of fats in the brain. Researchers from the Université de Montréal’s affiliated hospital research centre (the CRCHUM) and the University of British Columbia (UBC) have shown that neurons have their own lipid reserves, which are essential for regulating energy balance in the body. Led by researchers Thierry Alquier, researcher in the Cardiometabolic Theme and professor at the Université de Montréal Faculty of Medicine, and Elizabeth Rideout, a professor at the UBC Faculty of Medicine, the study reveals that these reserves, known as lipid droplets, play a key role in both neuronal function and the body’s energy balance.

A new perspective on brain fuel

The brain is recognized as a major control centre for appetite, body weight and energy expenditure. However, how neurons manage their own fuel supply remains poorly understood.

Until now, glucose was considered the primary source of energy for neurons, while lipids were mainly associated with membrane structure and cellular communication. The mechanisms through which neurons store and use fats remained largely unknown.

Lipid droplets, organelles composed primarily of triglycerides, had previously been observed mainly in pathological contexts, particularly in neurodegenerative diseases such as Alzheimer’s disease. Their presence in healthy neurons and their role under normal conditions were not well documented.

Reserves found in several species

Using an approach combining animal models with genetic tools, the teams have demonstrated that these lipid droplets are present and functional in species that are very distant from one another on an evolutionary level, ranging from invertebrates to vertebrates.

The research, to which PhD students Romane Manceau and Danie Majeur contributed, has identified enzymes and proteins that control how these reserves are formed and used, as well as their role in energy balance.

By blocking their use, the researchers observed significant effects: fat accumulation in worms and flies, and disruptions in food intake and energy expenditure in mice.

A direct impact on metabolism

The study focused specifically on two types of neurons involved in energy balance: AgRP neurons in the hypothalamus of mice and AKH neurons in flies.

By genetically disrupting the formation or utilization of lipid droplets in these neurons, the researchers demonstrated their direct influence on energy reserves, food intake and body weight.

These effects were observed in various species and appear to be more pronounced in males, suggesting that there is a sex-specific aspect to energy regulation.

An expanded cellular role

At the cellular level, the lipids released by these droplets influence membrane composition, support the functioning of both mitochondria—the cells’ “powerhouses”—and the endoplasmic reticulum, which is involved in protein synthesis and, ultimately, neuronal activity.

These findings are part of an emerging body of research suggesting that lipids can also serve as an energy source for neurons.

New avenues for research

By challenging the notion that glucose is the sole fuel for neurons, this study reveals a conserved mechanism that allows the brain to manage its own energy reserves and cellular components.

It paves the way for new research into the role of neuronal lipid metabolism in conditions such as obesity, type 2 diabetes and certain disorders of brain metabolism, as well as into the differences observed between the sexes.

The research was funded by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Fonds de recherche du Québec – Santé.

Author : Université de Montréal