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Triglycerides are an important fuel reserve for synapse function in the brain

Kumar, Mukesh, Wu, Yumei, Knapp, Justin, Pontius, Catherine L., Park, Daehun, Witte, Rose E., McAllister, Rachel, Gupta, Kallol, Rajagopalan, Kartik N., De Camilli, Pietro, Ryan, Timothy A.·2025·Nature Metabolism
DOI 10.1038/s42255-025-01321-xPMC PMC12286841

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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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  • Inability of neurons to mobilize fatty acids from triglycerides due to neuron-specific triglyceride lipase deficiency results in respiratory dysfunction and decreased ATP production, even at normal glucose metabolism.

    “Lipids as metabolic fuel came into recent focus with studies showing that the inability of neurons to mobilize fatty acids from triglycerides, due to neuron-specific triglyceride lipase deficiency, results in respiratory dysfunction and a decrease in ATP production, albeit at normal glucose metabolism47,48.”

    From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [47]

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Research works printed but not linked: 30

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Metadata

Authors
Kumar, M., Wu, Y., Knapp, J., Pontius, C. L., Park, D., Witte, R. E., McAllister, R., Gupta, K., Rajagopalan, K. N., De Camilli, P., & Ryan, T. A.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2025-07-01
Volume
7
Issue
7
Pages
1392-1403
ISSN
2522-5812
DOI
10.1038/s42255-025-01321-x
PMC
PMC12286841
Cited by
89
References
3
Language
en
Licence

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