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

IF 18.9 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L. Pontius, Daehun Park, Rose E. Witte, Rachel McAllister, Kallol Gupta, Kartik N. Rajagopalan, Pietro De Camilli, Timothy A. Ryan
{"title":"Triglycerides are an important fuel reserve for synapse function in the brain","authors":"Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L. Pontius, Daehun Park, Rose E. Witte, Rachel McAllister, Kallol Gupta, Kartik N. Rajagopalan, Pietro De Camilli, Timothy A. Ryan","doi":"10.1038/s42255-025-01321-x","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"3 1","pages":""},"PeriodicalIF":18.9000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s42255-025-01321-x","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0

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.

Abstract Image

甘油三酯是大脑突触功能的重要燃料储备
大脑的适当补充对维持认知功能至关重要,但脂肪酸(FA)燃烧在这一过程中的作用一直难以捉摸。本研究表明,神经元特异性甘油三酯脂肪酶、DDHD2(复杂遗传性痉挛性截瘫的遗传驱动因子)或线粒体脂质转运体CPT1的急性阻断,会导致成年雄性小鼠迅速出现昏迷。这些数据表明,体内神经元可能通过β-氧化不断地从脂滴(ld)中提取FAs,以支持神经元的生物能量学。我们发现,在游离的神经元中,电沉默或阻断DDHD2会导致神经元ld的积累,包括在神经末梢,并且来自轴突ld的FAs以活动依赖的方式进入线粒体,以驱动局部线粒体ATP的产生。这些数据表明,神经末梢可以在电活动期间利用ld提供代谢支持,并可能在体内支持神经元功能方面发挥关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Nature metabolism
Nature metabolism ENDOCRINOLOGY & METABOLISM-
CiteScore
27.50
自引率
2.40%
发文量
170
期刊介绍: Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信