bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–08–17
fourteen papers selected by
Regina F. Fernández, Johns Hopkins University



  1. J Neurochem. 2025 Aug;169(8): e70197
      The editorial "Embracing the Modern Biochemistry of Brain Metabolism" takes exception with some critics who "persist in refuting intercellular metabolic exchange", singling out our recent review "A bird's-eye view of glycolytic upregulation in activated brain: The major fate of lactate is release from activated tissue, not shuttling to nearby neurons". However, it is important to note that our review did not refute intercellular metabolic exchange or shuttles. The review only refuted the concept that most of the incremental neuronal energy needed to support increased signaling during activation is supplied by an astrocyte-to-neuron lactate shuttle (ANLS) as originally proposed more than 30 years ago. Like the authors of the editorial, we also advocate for a rigorous research agenda, and we agree that elucidating the intricate and dynamic intercellular metabolic exchanges in brain tissue, beyond merely lactate, is essential to advance clinical and neuroprotective treatments. However, we reject their claim that our review represents "a minority school of thought" that "continues to dispute this concept without offering compelling scientific proof". The evidence refuting a major role of the ANLS is in our detailed, fact-based review for interested neuroscientists to read and evaluate for themselves.
    Keywords:  ANLS; astrocyte; glucose; glycogen; lactate; neuron
    DOI:  https://doi.org/10.1111/jnc.70197
  2. Trends Endocrinol Metab. 2025 Aug 12. pii: S1043-2760(25)00152-3. [Epub ahead of print]
      Central nervous system (CNS) myelin may act as a dynamic energy store that supports brain metabolism; its consumption and replenishment is a newly recognized form of metabolic plasticity aimed at maintaining brain function upon limited glucose supply. In this forum article we propose that myelin dysfunctions may affect human health in aging and neurodegenerative diseases.
    Keywords:  aging; energy metabolism; myelin; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.tem.2025.07.006
  3. Int J Mol Sci. 2025 Jul 24. pii: 7149. [Epub ahead of print]26(15):
      Glycolysis and oxidative phosphorylation are the main pathways of cellular energy production. Glucose is metabolized via glycolysis to generate pyruvate, which, under anaerobic conditions, is converted into lactate, while, under aerobic conditions, pyruvate enters mitochondria for oxidative phosphorylation to produce more energy. Accordingly, mitochondrial dysfunction disrupts the energy balance. Lactate, historically perceived as a harmful metabolic byproduct. However, emerging research indicates that lactate has diverse biological functions, encompassing energy regulation, epigenetic remodeling, and signaling activities. Notably, the 2019 study revealed the role of lactate in regulating gene expression through histone and non-histone lactylation, thereby influencing critical biological processes. Metabolic reprogramming is a key adaptive mechanism of cells responding to stresses. The Warburg effect in tumor cells exemplifies this, with glucose preferentially converted to lactate for rapid energy, accompanied by metabolic imbalances, characterized by exacerbated aerobic glycolysis, lactate accumulation, suppressed mitochondrial oxidative phosphorylation, and compromised mitochondrial function, ultimately resulting in a vicious cycle of metabolic dysregulation. As molecular bridges connecting metabolism and epigenetics, lactate and lactylation offer novel therapeutic targets for diseases like cancer and neurodegenerative diseases. This review summarizes the interplay between metabolic reprogramming and mitochondrial dysfunction, while discussing lactate and lactylation's mechanistic in the pathogenesis of related diseases.
    Keywords:  epigenetics; lactate; lactylation; metabolic reprogramming; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms26157149
  4. Brain. 2025 Aug 06. pii: awaf267. [Epub ahead of print]
      Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) has shown potential therapeutic benefits in individuals with Alzheimer's disease (AD). These effects are widely presumed to be mediated by hepatic conversion of MCT into circulating ketones. However, the physiological and cellular mechanisms underlying the benefits of MCT remain understudied, particularly in the context of AD. Here, we investigated the cellular and molecular changes occurring in the brain and systemically in response to dietary supplementation with MCT versus a ketogenic diet (KD). The experimental design consisted of comparing a 70% carbohydrate control diet to either a control diet supplemented with 10% MCT or a carbohydrate-free high fat KD. Diets were tested in two AD mouse models, slow-progressing 3xTg-AD mice that model pre-symptomatic/early stages and rapidly-progressing 5xFAD mice that model late stages of the disease. We found that MCT supplementation and KD both improved hippocampal-dependent spatial learning and memory, increased dendritic spine density of hippocampal neurons, and modulated hippocampal expression of genes associated with mitochondrial functions, synaptic structure, and insulin signaling in AD mouse models. However, unlike KD, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT enhanced the peripheral insulin response of AD mice, while KD conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain, and adiposity. The systemic metabolic disturbances of AD mice correlated with transcriptomic alterations in hepatic lipid metabolism and ketogenesis genes and increased lipid droplet accumulation. These liver metabolic abnormalities were partially reversed by both MCT supplementation and KD, but in distinct ways. Notably, KD selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression while MCT down-regulated expression of cholesterol-related genes. Collectively, these findings reveal that MCT supplementation in the context of AD improves cognition and systemic metabolism without elevating circulating ketone levels.
    Keywords:  Alzheimer’s disease; cognition; ketogenic diet; ketones; medium-chain triglycerides; peripheral metabolism
    DOI:  https://doi.org/10.1093/brain/awaf267
  5. Neural Regen Res. 2025 Aug 13.
      This study investigated the neuroprotective effects of lactate in subarachnoid hemorrhage, a severe cerebrovascular disease that is commonly caused by arterial aneurysm rupture and has limited early treatment options. Lactate, a metabolic byproduct, has been shown to have neuroprotective properties, including enhancing cerebral microcirculation and reducing intracranial pressure in acute brain injury patients. However, the protective mechanisms of lactate in subarachnoid hemorrhage remain unknown. In this study, we showed that lactate alleviates early brain damage in subarachnoid hemorrhage by promoting neuronal lipid synthesis and the formation of lipid droplets in astrocytes. In vivo experiments using a subarachnoid hemorrhage mouse model showed that lactate treatment significantly improved neurological scores, reduced brain inflammation, and promoted lipid droplet formation in astrocytes within 24 hours. Lactate treatment increased free fatty acids levels in the brain. The results suggest that astrocytes absorbed these free fatty acids and converted them into lipid droplets, thus reducing cellular lipotoxicity. Moreover, lactate enhanced the antiapoptotic capacity of astrocytes by upregulating the expression of PLIN5, a protein crucial for lipid droplet formation. The inhibition of lipid synthesis or lipid droplet formation counteracted the neuroprotective effects of lactate, indicating that lactate's protective role is closely linked to lipid metabolism and lipid droplet formation. In vitro experiments on HT22 neuronal cells exposed to hemin-an agent used to simulate subarachnoid hemorrhage injury-demonstrated that lactate mitigated cellular damage by reducing lipid peroxidation and preserving mitochondrial membrane potential. Lactate treatment in HT22 cells and astrocytes also showed that inhibition of lipid synthesis or lipid droplet formation reversed its protective effects, further emphasizing the importance of lipid metabolism in the neuroprotective action of lactate. This study provides insights into the neuroprotective mechanisms of lactate in subarachnoid hemorrhage. It indicates that lactate plays a role in promoting lipid synthesis in neurons and enhancing lipid droplet formation in astrocytes, thus mitigating brain damage and improving cell survival. These findings suggest that lactate, through its regulation of lipid metabolism, could be a potential therapeutic agent for subarachnoid hemorrhage.
    Keywords:  PLIN5; apoptosis; astrocytes; free fatty acids; lactate; lipid droplets; lipid metabolism; neuronal lipid synthesis; neuroprotection; subarachnoid hemorrhage
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01543
  6. Imaging Neurosci (Camb). 2024 ;pii: imag-2-00305. [Epub ahead of print]2
      Lactate has increasingly been recognized as both an important fuel source and a signaling molecule within the brain. Alterations in brain lactate levels are associated with various neurological diseases. Thus, there is great interest in thein vivodetection and measurement of cerebral lactate levels in animals used for investigation of normal brain function and models of disease. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive technique used to measure lactate and other metabolites within the brain. However, lactate can be difficult to detect with conventional1H-MRS due to its low abundance and spectral overlap with lipids. In addition, volatile anesthetics used during image acquisition increase lactate production, potentially masking any subtle physiological changes in lactate levels. Here, we made use of a transgenic mouse model in which expression of lactate dehydrogenase A (Ldha), the rate-limiting enzyme of lactate production, was induced within cortical and hippocampal neurons. Unexpectedly,1H-MRS analysis, under typical isoflurane-induced anesthesia of 4% induction followed by 1.6-2% maintenance, revealed no significant elevation of hippocampal lactate levels in neuronalLdhainduction mice compared to control mice. In contrast,1H-MRS analysis, using an isoflurane titration protocol in which mice were sequentially exposed to 1.6%, 2%, and then finally 3% isoflurane, revealed significantly higher hippocampal lactate levels inLdhatransgenic mice compared to controls. In addition, significantly fewer mice were required to detect differences in lactate levels using the isoflurane titration protocol compared to conventional isoflurane-induced anesthesia. Our findings highlight the importance of controlling for the effects of anesthesia when detecting changes in hippocampal lactate levelsin vivoand offer a novel protocol for enhanced cerebral lactate detection.
    Keywords:  1 H-MRS ; anesthetic; hippocampus; isoflurane; lactate; lactate dehydrogenase
    DOI:  https://doi.org/10.1162/imag_a_00305
  7. bioRxiv. 2025 Jul 17. pii: 2025.07.11.664443. [Epub ahead of print]
      Alzheimer's disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify cell-type specific master metabolic regulators of AD underlying the metabolic alterations in AD, we introduce scFUMES ( s ingle c ell FU nctional ME tabolite- S ensor), an algorithm integrating single-cell RNA sequencing, interactomics, genomics, transcriptomics, and metabolomics from human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. Collectively, scFUMES systematically maps AD master metabolic regulators, offering insights into cellular metabolic heterogeneity and therapeutic strategies for AD and other AD-related dementia if broadly applied.
    DOI:  https://doi.org/10.1101/2025.07.11.664443
  8. J Cereb Blood Flow Metab. 2025 Aug 13. 271678X251364136
      Axonal injuries commonly contribute to poor functional outcomes following traumatic brain injury (TBI). To assess cerebral blood flow (CBF) and energy metabolic disturbances in a TBI model of widespread axonal injury, we exposed 105 adult mice to the central (midline) fluid percussion injury (cFPI) diffuse TBI model, or sham injury, and used 9.4 T magnetic resonance (MR) arterial spin labeling (ASL), cortical and hippocampal mitochondrial respiration, and hippocampal MR spectroscopy at 1- and 7-days post-injury (dpi). Widespread, bilateral CBF reductions were observed at day 1 dpi, changes that were normalized by 7 dpi. However, cortical and hippocampal mitochondrial respiration and reactive oxygen species (ROS) production was not significantly altered at 1 and 7 dpi. Moreover, hippocampal volumes, evaluated by MRI, were not altered by cFPI, and by immunohistochemistry only a few apoptotic hippocampal cells were observed. By MRS, evidence of delayed (7 dpi) membrane disruption (phosphocholine and glycerophosphocholine) and glutamate/glutamine increase were observed. While widespread traumatic axonal pathology associated with functional impairments is observed in this TBI model, early CBF alterations were transient and did not translate into significant energy metabolic disturbances. Instead, the delayed hippocampal metabolite changes observed by MRS may contribute to the functional impairment observed in this diffuse TBI model.
    Keywords:  Traumatic brain injury (TBI); axonal injury; central fluid percussion injury; cerebral blood flow; energy metabolism; mitochondria
    DOI:  https://doi.org/10.1177/0271678X251364136
  9. J Neurosci. 2025 Aug 11. pii: e1529242025. [Epub ahead of print]
      The neurotransmitter release and the synaptic vesicle cycle require a specific lipidic composition of presynaptic and vesicle membranes. Phospholipids with long-chain acyl groups are necessary to confer to membranes the physical properties necessary for synaptic transmission. Elovl5 is crucial for the elongation of polyunsaturated fatty acids (PUFAs) beyond 18-carbon atoms, and its deletion or mutation causes cerebellar motor deficits in humans and mice. In the mouse cerebellum of both sexes, deletion of Elovl5 increased 18- and 20-carbon atoms PUFAs, decreased long-chain PUFAs, and increased saturated and monounsaturated fatty acids. Electrophysiological recordings in Purkinje cells revealed that basal synaptic transmission was preserved in Elovl5 knockout mice. However, the recovery from depression of the climbing fiber synapse lacked the fast phase, suggesting a deficit in replenishment of the readily releasable pool of synaptic vesicles. The parallel fiber synapse showed slower replenishment rate of the readily releasable pool at relatively high but physiological frequencies of 50 and 100 Hz. Endocannabinoids contain a long-chain PUFA, and in Purkinje cells, they mediate the synaptically induced suppression of excitation (SSE). In Elovl5 knockout mice, SSE had a shorter duration, suggesting a role of Elovl5 in this form of synaptic plasticity. Accordingly, we show dramatic change in length and level of unsaturation of lipids in synaptosomes isolated from Elovl5 knockout mice. These results suggest that the shift in PUFA lipidic species caused by the absence of Elovl5, in the cerebellar cortex, is responsible for specific deficits in neurotransmitter release.Significance Statement The gene ELOngase of Very-Long chain fatty acids type 5 (ELOVL5) encodes an enzyme responsible for producing polyunsaturated fatty acids (PUFAs), which are essential to maintain presynaptic membrane flexibility during synaptic transmission. Mutations of ELOVL5 cause Spinocerebellar ataxia type 38 (SCA38, MIM# 615957). This study shows that the complete absence of Elovl5 in mice results in significant alterations in cerebellar excitatory presynaptic mechanisms. Specifically, we found deficits in replenishment of the readily releasable pool of synaptic vesicles at synapses impinging on Purkinje cells, along with disruption of the endocannabinoid-dependent short-term plasticity. These dysfunctions were paralleled by marked changes in lipidic composition of cerebellar tissues, including cerebellar synaptosomes, highlighting the critical role of Elovl5 in cerebellar function.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1529-24.2025
  10. Nat Neurosci. 2025 Aug 11.
      Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.
    DOI:  https://doi.org/10.1038/s41593-025-02032-y
  11. Cells. 2025 Aug 05. pii: 1202. [Epub ahead of print]14(15):
      Neuroinflammation is the major contributor to the pathology of neonatal hypoxic-ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen-glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1b and rescued OGD-mediated downregulation of mitochondrial iron-sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury.
    Keywords:  hypoxia–ischemia; microglia; mitochondrial dysfunction; neuroinflammation
    DOI:  https://doi.org/10.3390/cells14151202
  12. Front Aging. 2025 ;6 1628835
       Introduction: The ketogenic diet (KD) increases mouse lifespan and health span, and improves late-life memory. This raises the question regarding the mechanism behind this effect. In mice on a KD, blood beta-hydroxybutyrate (BHB) levels uniquely rise higher than those of mice on a control diet (CD). BHB is therefore considered a key signaling and metabolic mediator of KD's effects and benefits. BHB crossed the blood-brain barrier and rescued memory, improved cognitive function, and increased neuronal plasticity in two different mouse models of Alzheimer's disease (PS1/APP and 5XFAD). At the cellular level, microglia are thought to play a critical role in the physiologic basis of memory due to their important role in synaptic development, plasticity, and connectivity. Conversely, microglial dysfunction and inflammation are connected to cognitive decline and neurodegenerative diseases. Because of this, one explanatory hypothesis for these positive therapeutic observations in mice is that the KD and BHB drive memory and longevity benefits through their anti-inflammatory actions on microglia.
    Method: We investigated the concentration dependence of BHB's antiinflammatory effects in BV2 microglial cells. We focused on 1.5 mM BHB, which reflects blood levels in mice and humans on a KD.
    Results: At this concentration, BHB significantly and concentration-dependently decreased the following: 1) inflammatory cytokine expression (IL-6, TNF-α, and IL-1β), 2) inflammatory morphological changes, and 3) activation of p-ERK and p-p38MAPK, which are key pathways involved in microglial inflammation. We show, for the first time, that the expression of Alzheimer's risk gene TREM2 is modified by dietarily-achievable 1.5 mM BHB. BHB's anti-inflammatory, morphological, biochemical, and TREM2 effects were blocked by a monocarboxylate transporter (MCT) inhibitor, supporting the idea that BHB must enter microglia to elicit some of its anti-inflammatory effects.
    Discussion: These results support the hypothesis that blood BHB levels achievable on a KD elicit significant concentration-dependent anti-inflammatory effects in microglia. Increasing BHB concentration through sustained KD, or BHB supplements, may lower microglial inflammatory tone and provide benefits in age-related memory loss.
    Keywords:  Alzheimer’s; Alzheimer’s disease; BHB; TREM2; beta-hydroxybutyrate; ketogenic diet; ketone; microglia
    DOI:  https://doi.org/10.3389/fragi.2025.1628835
  13. Pharmacol Ther. 2025 Aug 07. pii: S0163-7258(25)00121-4. [Epub ahead of print]274 108909
      Hydroxycarboxylic acid receptor 2 (HCAR2) is a G-protein-coupled receptor initially identified for its role in lipid metabolism. Beyond its classical metabolic functions, HCAR2 plays a pivotal role in chronic inflammatory diseases, neurometabolic disorders, and pain modulation. Evidence from preclinical studies suggest that when endogenously activated by β-hydroxybutyrate and pharmacologically by niacin and its derivatives, HCAR2 attenuates microglial reactivity, suppress pro-inflammatory cytokine release, and modulate neuronal excitability, by offering neuroprotective benefits in neurological disorders and chronic pain. Additionally, emerging data highlight its involvement in gut-brain axis regulation, linking dietary interventions and microbiota-derived metabolites to Central Nervous System function. The development of selective HCAR2 agonists with improved pharmacokinetic and safety profiles holds promise for treatments targeting both peripheral and central pathologies. This review explores the structural and functional aspects of HCAR2, and describe novel synthetic HCAR2 agonists, by emphasizing its therapeutic potential across a spectrum of metabolic and neuroinflammatory disorders.
    Keywords:  Chronic pain; Gut-brain axis; Hydroxyl carboxylic acid receptor-2; Neurodegenerative disorders; Neuroinflammation; Neurometabolic dysfunctions; Β-Hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.pharmthera.2025.108909
  14. Neural Regen Res. 2025 Aug 13.
      Microglia, lipids, and their interaction are found to play important roles in post-stroke immunity. Microglia are sensitive to detect environment change in injured brain. Activated microglia undergo phenotypical remodeling and trigger complex signal cascades to regulate immune responses after stroke. Lipids including peripheral lipid metabolism and lipid droplet biogenesis are involved in the control of microglia functions, such as activation, phagocytosis, proliferation, and pro-inflammation. In this review, we explore new scope of microglia and lipids in immune regulation of stroke. Implication of peripheral lipid metabolism after stroke is mentioned and advances in microglia-lipid interaction are discussed. We give a special focus on how diet and gut microbiome influence neuroinflammation system via gut-brain axis, and how these processes associate with the risk and outcome of stroke. Moreover, we reviewed the therapeutic targets related to lipid metabolism and microglial modulation after stroke. These can provide a prospective strategy for more efficient and safer treatment for ischemic and hemorrhagic stroke.
    Keywords:  cerebral hemorrhage; diet; gut microbiome; inflammation; ischemic stroke; lipid; metabolism; microglia; regeneration; therapeutic targets
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01523