Triglycerides are an important fuel reserve for synapse function in the brain, 2025, Kumar et al

[Mij]

Abstract​

Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice.

These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production.

These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
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[jnmaciuch]

That’s fascinating, I’ll need to read more in depth. If the findings hold up it means that we’ve been absolutely incorrect about the idea that the brain only uses glucose as a fuel source. It also means that measurements of brain metabolic activity using glucose tracing have only been looking at half the story.

 

[Creekside]

It also means that measurements of brain metabolic activity using glucose tracing have only been looking at half the story.

I think "Its not what you don't know, but what you do know that is wrong" applies here. Imagine that ME involves FA metabolism in brain cells, but "everyone knows that there's no need to check FA activity".

 

[Utsikt]

That’s fascinating, I’ll need to read more in depth. If the findings hold up it means that we’ve been absolutely incorrect about the idea that the brain only uses glucose as a fuel source. It also means that measurements of brain metabolic activity using glucose tracing have only been looking at half the story.

How would you be able to test this in humans?

 

[jnmaciuch]

How would you be able to test this in humans?

Theoretically it might be possible to do PET scans with labeled fats instead of glucose. But this is not something I have any expertise in, there might be issues with feasibility that I'm not aware of. I'm not even sure if fatty acids in the circulation reach the brain in their original form, or if they have to get broken down first and then get re-synthesized into a bunch of various molecules.

 

[jnmaciuch]

I think an interesting facet of this paper is the finding that fatty acid oxidation, glycolysis, and oxidative phosphorylation can more or less be switched out in neurons to compensate for each other if one method is unavailable. This seems pretty consistent with other cell types which utilize all three mechanisms.

The interesting part is that inhibition of fatty acid oxidation on its own was enough to trigger torpor--the lethargic state associated with hibernation. Meaning that changes in metabolism in the brain are capable of inducing substantial behavioral changes even if you never end up with a critical lack of neuronal ATP production (and subsequent cell death from critically low ATP).

The paper speculates that this is the mechanism by which food restriction induces hibernation in mammals, which is known to occur through the hypothalamus (and given the similarity of phenotype in food restriction vs. fatty acid oxidation blockade, it's a convincing line of argument even though the paper doesn't provide definitive proof on that). Whether this is induced by the hypothalamus sensing metabolic capacity in other parts of the brain/body or by direct metabolic alterations in hypothalamic neurons is still unknown, though.