bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022–03–06
48 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. N-3 PUFA Deficiency Affects the Ultrastructural Organization and Density of White Matter Microglia in the Developing Brain of Male Mice.
  2. Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer's Disease.
  3. Glucose as a carbon source to synthesize palmitate de novo in the adult rodent brain: Adding to the carbon recycling story in the brain.
  4. The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.
  5. ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models.
  6. Epoxyeicosatrienoic acids and soluble epoxide hydrolase in physiology and diseases of the central nervous system.
  7. Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson's Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway.
  8. Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson's disease.
  9. Coactivator-associated arginine methyltransferase 1 controls oligodendrocyte differentiation in the corpus callosum during early brain development.
  10. Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.
  11. Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.
  12. Therapeutic Induction of Energy Metabolism Reduces Neural Tissue Damage and Increases Microglia Activation in Severe Spinal Cord Injury.
  13. The Effect of Aging on Brain Glucose Metabolic Connectivity Revealed by [18F]FDG PET-MR and Individual Brain Networks.
  14. Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains.
  15. Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.
  16. Ginsenoside Rg1 Reduced Microglial Activation and Mitochondrial Dysfunction to Alleviate Depression-Like Behaviour Via the GAS5/EZH2/SOCS3/NRF2 Axis.
  17. Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders.
  18. Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.
  19. Gender-Related Differences in Regional Cerebral Glucose Metabolism in Normal Aging Brain.
  20. Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle-Aged Adults.
  21. A Nutrient Formulation Affects Developmental Myelination in Term Infants: A Randomized Clinical Trial.
  22. Corrigendum to: De novo Lipogenesis in Astrocytes Promotes the Repair of Blood-Brain Barrier after Transient Cerebral Ischemia Through Interleukin-33 [Neuroscience 481 (2022) 85-98].
  23. Shielded geomagnetic field accelerates glucose consumption in human neuroblastoma cells by promoting anaerobic glycolysis.
  24. Isoform- and cell-state-specific lipidation of ApoE in astrocytes.
  25. Time-dependent influence of high glucose environment on the metabolism of neuronal immortalized cells.
  26. The Impact of Electroacupuncture Early Intervention on the Brain Lipidome in a Mouse Model of Post-traumatic Stress Disorder.
  27. Glucose infusion suppresses acute restraint stress-induced peripheral and central sympathetic responses in rats.
  28. Glycolytic and Krebs cycle enzymes activity in rat prefrontal cortex, hippocampus, and striatum after single and repeated NMDA inhibition by MK-801.
  29. Ceramide kinase knockout ameliorates multiple sclerosis-like behaviors and demyelination in cuprizone-treated mice.
  30. Clinical 1H MRS in childhood neurometabolic diseases - part 2: MRS signatures.
  31. Protective effect of curcumin against rotenone-induced substantia nigra pars compacta neuronal dysfunction.
  32. CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.
  33. Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model.
  34. Quinolinic Acid Impairs Redox Homeostasis, Bioenergetic, and Cell Signaling in Rat Striatum Slices: Prevention by Coenzyme Q10.
  35. Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord.
  36. Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
  37. Effects of alpha lipoic acid on metabolic syndrome: A comprehensive review.
  38. Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.
  39. Pregnancy-induced alterations of 1-carbon metabolism and significance for maternal nutrition requirements.
  40. Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism.
  41. Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin.
  42. Metabolomics and biochemical alterations caused by pleiotrophin in the 6-hydroxydopamine mouse model of Parkinson's disease.
  43. Disrupted choline clearance and sustained acetylcholine release in vivo by a common choline transporter coding variant associated with poor attentional control in humans.
  44. Drosophila Sirtuin 6 mediates developmental diet-dependent programming of adult physiology and survival.
  45. Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits.
  46. A Patient with Recurrent Severe Hypoglycemic Attacks and Mitochondrial Complex III Deficiency, Nuclear Type 3: a Novel UQCRB Variant.
  47. Transcutaneous auricular vagal nerve stimulation inhibits limbic-regional P2X7R expression and reverses depressive-like behaviors in Zucker diabetic fatty rats.
  48. Brain lipidomics and neurodevelopmental outcomes in intrauterine growth restricted piglets fed dairy or vegetable fat diets.
  1. Front Cell Neurosci. 2022 ;16 802411
    N-3 PUFA Deficiency Affects the Ultrastructural Organization and Density of White Matter Microglia in the Developing Brain of Male Mice.
    Fanny Decoeur, Katherine Picard, Marie-Kim St-Pierre, Andrew D Greenhalgh, Jean-Christophe Delpech, Alexandra Sere, Sophie Layé, Marie-Eve Tremblay, Agnès Nadjar.
      Over the last century, westernization of dietary habits has led to a dramatic reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). In particular, low maternal intake of n-3 PUFAs throughout gestation and lactation causes defects in brain myelination. Microglia are recognized for their critical contribution to neurodevelopmental processes, such as myelination. These cells invade the white matter in the first weeks of the post-natal period, where they participate in oligodendrocyte maturation and myelin production. Therefore, we investigated whether an alteration of white matter microglia accompanies the myelination deficits observed in the brain of n-3 PUFA-deficient animals. Macroscopic imaging analysis shows that maternal n-3 PUFA deficiency decreases the density of white matter microglia around post-natal day 10. Microscopic electron microscopy analyses also revealed alterations of microglial ultrastructure, a decrease in the number of contacts between microglia and myelin sheet, and a decreased amount of myelin debris in their cell body. White matter microglia further displayed increased mitochondrial abundance and network area under perinatal n-3 PUFA deficiency. Overall, our data suggest that maternal n-3 PUFA deficiency alters the structure and function of microglial cells located in the white matter of pups early in life, and this could be the key to understand myelination deficits during neurodevelopment.
    Keywords:  electron microscopy; microglia; myelin; n-3 PUFA; neurodevelopment
    DOI:  https://doi.org/10.3389/fncel.2022.802411
  2. Front Behav Neurosci. 2021 ;15 778456
    Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer's Disease.
    Brandon Emanuel León, Shinwoo Kang, Gabriela Franca-Solomon, Pei Shang, Doo-Sup Choi.
      Mitochondria are essential organelles central to various cellular functions such as energy production, metabolic pathways, signaling transduction, lipid biogenesis, and apoptosis. In the central nervous system, neurons depend on mitochondria for energy homeostasis to maintain optimal synaptic transmission and integrity. Deficiencies in mitochondrial function, including perturbations in energy homeostasis and mitochondrial dynamics, contribute to aging, and Alzheimer's disease. Chronic and heavy alcohol use is associated with accelerated brain aging, and increased risk for dementia, especially Alzheimer's disease. Furthermore, through neuroimmune responses, including pro-inflammatory cytokines, excessive alcohol use induces mitochondrial dysfunction. The direct and indirect alcohol-induced neuroimmune responses, including pro-inflammatory cytokines, are critical for the relationship between alcohol-induced mitochondrial dysfunction. In the brain, alcohol activates microglia and increases inflammatory mediators that can impair mitochondrial energy production, dynamics, and initiate cell death pathways. Also, alcohol-induced cytokines in the peripheral organs indirectly, but synergistically exacerbate alcohol's effects on brain function. This review will provide recent and advanced findings focusing on how alcohol alters the aging process and aggravates Alzheimer's disease with a focus on mitochondrial function. Finally, we will contextualize these findings to inform clinical and therapeutic approaches towards Alzheimer's disease.
    Keywords:  Alzheimer’s disease; aging; alcohol use disorder; dementia; mitochondria; morphology
    DOI:  https://doi.org/10.3389/fnbeh.2021.778456
  3. J Neurochem. 2022 Feb 27.
    Glucose as a carbon source to synthesize palmitate de novo in the adult rodent brain: Adding to the carbon recycling story in the brain.
    Eric J Murphy.
      While brain glucose metabolism is known to contribute the carbons to support brain saturated and monounsaturated fatty biosynthesis de novo in the developing brains of young rodents, such a contribution to fatty acid biosynthesis in the adult brain is poorly understood. Recent work from the Bazinet laboratory illuminates the role of brain glucose metabolism in providing a carbon source from which palmitic acid is synthesized. In "The Majority of Brain Palmitic Acid is Maintained by Lipogenesis from Dietary Sugars and is Augmented in Offspring fed low Palmitic Acid Levels from Birth", the Bazinet lab demonstrates the importance of glucose as a key contributing source of carbon for brain palmitic synthesis and that a low palmitate diet exacerbates its utilization for brain palmitate synthesis de novo. Further, this impact is found in male mice rather than female mice, which adds an additional layer of importance. Mammals are known to conserve carbon and the brain has the ability to convert a variety of carbon sources to needed molecules, depending on the physiological needs of the brain. Overall, this paper contributes an important missing piece of the puzzle regarding carbon recycling in the brain and is a key piece of evidence that indeed the adult mammalian brain can convert glucose to carbons for use in saturated fatty acid synthesis.
    DOI:  https://doi.org/10.1111/jnc.15592
  4. Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00074-0. [Epub ahead of print]
    The neuroprotective effects of intermittent fasting on brain aging and neurodegenerative diseases via regulating mitochondrial function.
    Yihang Zhao, Mengzhen Jia, Weixuan Chen, Zhigang Liu.
      Intermittent fasting (IF) has been studied for its effects on lifespan and lifespan as well as the prevention or delay of age-related diseases upon the regulation of metabolic pathways. Mitochondria participate in key metabolic pathways and play important roles in maintaining intracellular signaling networks that modulate various cellular functions. Mitochondrial dysfunction has been described as an early feature of brain aging and neurodegeneration. Although IF has been shown to prevent brain aging and neurodegeneration, the mechanism is still unclear. This review focuses on the mechanisms by which IF improves mitochondrial function, which plays a central role in brain aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The cellular and molecular mechanisms of IF in brain aging and neurodegeneration involve activation of adaptive cellular stress responses and signaling- and transcriptional pathways, thereby enhancing mitochondrial function, by promoting energy metabolism and reducing oxidant production.
    Keywords:  Brain aging; Intermittent fasting; Mitochondrial dysfunction; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.021
  5. Nat Commun. 2022 Mar 02. 13(1): 1121
    ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models.
    Yuanyuan Zhao, Di Hu, Rihua Wang, Xiaoyan Sun, Philip Ropelewski, Zita Hubler, Kathleen Lundberg, Quanqiu Wang, Drew J Adams, Rong Xu, Xin Qi.
      Predisposition to Alzheimer's disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.
    DOI:  https://doi.org/10.1038/s41467-022-28769-9
  6. Chin J Physiol. 2022 Jan-Feb;65(1):65(1): 1-11
    Epoxyeicosatrienoic acids and soluble epoxide hydrolase in physiology and diseases of the central nervous system.
    Yi-Min Kuo, Yi-Hsuan Lee.
      Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid. The biological activity of EETs is terminated when being metabolized by soluble epoxide hydrolase (sEH), a process that serves as a key regulator of tissue EETs levels. EETs act through several signaling pathways to mediate various beneficial effects, including anti-inflammation, anti-apoptosis, and anti-oxidation with relieve of endoplasmic reticulum stress, thereby sEH has become a potential therapeutic target in cardiovascular disease and cancer therapy. Enzymes for EET biosynthesis and metabolism are both widely detected in both neuron and glial cells in the central nervous system (CNS). Recent studies discovered that astrocyte-derived EETs not only mediate neurovascular coupling and neuronal excitability by maintaining glutamate homeostasis but also glia-dependent neuroprotection. Genetic ablation as well as pharmacologic inhibition of sEH has greatly helped to elucidate the physiologic actions of EETs, and maintaining or elevating brain EETs level has been demonstrated beneficial effects in CNS disease models. Here, we review the literature regarding the studies on the bioactivity of EETs and their metabolic enzyme sEH with special attention paid to their action mechanisms in the CNS, including their modulation of neuronal activity, attenuation of neuroinflammation, regulation of cerebral blood flow, and improvement of neuronal and glial cells survival. We further reviewed the recent advance on the potential application of sEH inhibition for treating cerebrovascular disease, epilepsy, and pain disorder.
    Keywords:  Cerebrovascular disease; epilepsy; epoxyeicosatrienoic acids; neuroglia; neuroinflammation; neuronal excitability; neuroprotection; neurovascular coupling; pain disorder; soluble epoxide hydrolase
    DOI:  https://doi.org/10.4103/cjp.cjp_80_21
  7. Front Neurol. 2021 ;12 646817
    Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson's Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway.
    Min Chen, Li Peng, Ping Gong, Xiaoli Zheng, Tao Sun, Xiaoqiao Zhang, Jiangtao Huo.
      Parkinson's disease (PD) is a prevailing neurodegenerative disorder. Baicalein has neuroprotective effects on PD animals, but its mechanism is not clarified. We explored baicalein effects on PD rats. PD rat models were established by injecting 6-hydroxydopamine into the striatum of substantia nigra on the left side of the rat brain and treated with baicalein. Dopamine (DA) content, neuronal apoptosis, neuronal injury, neuronal mitochondria, and autophagy were assessed. Baicalein-treated PD rats were treated with autophagy inhibitor 3-methyladenine to identify the role of autophagy in PD. PD rats were injected with AgomiR-30b-5p or sh-SIRT1 plasmids and treated with baicalein. PD rats elicited decreased neurological score and DA secretion of the striatum, increased neuronal apoptosis, and injury, and reduced number of mitochondria and autophagy, whereas baicalein alleviated neuronal injury and partly recovered mitochondrial dysfunction, 3-methyladenine inhibited the protection of baicalein. miR-30b-5p was elevated and SIRT1 was diminished in PD rats and inhibited by baicalein. miR-30b-5p targeted SIRT1. miR-30b-5p overexpression or SIRT1 silencing annulled the protection of baicalein. The phosphorylation level of AMPK in the substantia nigra of PD rats was decreased and mTOR was increased, whereas baicalein annulled these trends. Briefly, baicalein activated mitochondrial autophagy via miR-30b-5p and the SIRT1/AMPK/mTOR pathway, thus protecting PD rats.
    Keywords:  AMPK/mTOR pathway; Parkinson's disease; SIRT1; baicalein; miR-30b-5p; mitochondrial autophagy; striatum
    DOI:  https://doi.org/10.3389/fneur.2021.646817
  8. Mol Med. 2022 Mar 04. 28(1): 28
    Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson's disease.
    Jannik Prasuhn, Martin Göttlich, Friederike Gerkan, Sofia Kourou, Britt Ebeling, Meike Kasten, Henrike Hanssen, Christine Klein, Norbert Brüggemann.
       BACKGROUND: The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson's disease.
    METHODS: Thirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31phosphorus magnetic resonance spectroscopy imaging. SWI contrast-to-noise ratios served as a measure for brain iron deposition in the putamen, caudate, globus pallidus, and thalamus and were used in a multiple linear regression model to predict in-vivo energy metabolite ratios.
    RESULTS: Subcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects.
    CONCLUSIONS: Our study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.
    Keywords:  Iron; Mitochondria; Parkinson's disease (PD)
    DOI:  https://doi.org/10.1186/s10020-021-00426-9
  9. Dev Neurobiol. 2022 Feb 26.
    Coactivator-associated arginine methyltransferase 1 controls oligodendrocyte differentiation in the corpus callosum during early brain development.
    Yugo Ishino, Shoko Shimizu, Masaya Tohyama, Shingo Miyata.
      Protein arginine methylation has been recognized as one of key post-translational modifications for refined protein functions, mediated by protein arginine methyltransferases (Prmts). Coactivator-associated arginine methyltransferase (Carm1, also known as Prmt4) participates in various cellular events, such as cell survival, proliferation, and differentiation through its protein arginine methylation activities. Carm1 regulates cell proliferation of a neuronal cell line and is reportedly expressed in the mammalian brain. However, its detailed function in the central nervous system, particularly in glial cells, remains largely unexplored. In this study, Carm1 exhibited relatively high expression in oligodendrocyte (OL) lineage cells present in the corpus callosum of the developing brain, followed by a remarkable downregulation after active myelination. The suppression of Carm1 activity by inhibitors in isolated oligodendrocyte precursor cells (OPCs) reduced the number of Ki67-expressing and BrdU-incorporated proliferating cells. Furthermore, Carm1 inactivation attenuated OL differentiation, as determined by the expression of Plp, a reliable myelin-related marker. It also impaired the extension of OL processes, accompanied by a significant reduction in gene expression related to OL differentiation and myelination, such as Sox10, Cnp, Myrf, and Mbp. In addition, OLs co-cultured with embryonic dorsal root ganglia neurons demonstrated that Carm1 activity is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons, and the induction of the clustering of Caspr, a node of Ranvier structural molecule. Thus, we propose that Carm1 is an essential molecule for the development of OPCs and OLs during brain development. This article is protected by copyright. All rights reserved.
    Keywords:  Carm1; arginine methylation; brain development; differentiation; myelination; oligodendrocyte; protein arginine methyltransferase
    DOI:  https://doi.org/10.1002/dneu.22871
  10. Oxid Med Cell Longev. 2022 ;2022 3644318
    Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.
    Baoliang Ren, Tianyun Zhang, Qiqing Guo, Jing Che, Yunxiao Kang, Rui Cui, Yu Wang, Xiaoming Ji, Guoliang Zhang, Geming Shi.
      Reduced testosterone level is a common feature of aging in men. Aging, as a risk factor for several neurodegenerative disorders, shows declined mitochondrial function and downregulated mitochondrial biogenesis and mitochondrial dynamics. Mitochondrial biogenesis and mitochondrial dynamics are crucial in maintaining proper mitochondrial function. Supplementation with testosterone is conducive to improving mitochondrial function of males during aging. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of redox homeostasis, is involved in the ameliorative effects of testosterone supplementation upon aging. To explore Nrf2 role in the effects of testosterone supplementation on mitochondrial function during aging, we studied the efficiency of testosterone supplementation in improving mitochondrial function of Nrf2 knockout- (KO-) aged male mice by analyzing the changes of mitochondrial biogenesis and mitochondrial dynamics. It was found that wild-type- (WT-) aged male mice showed low mitochondrial function and expression levels of PGC-1α, NRF-1\NRF-2, and TFAM regulating mitochondrial biogenesis, as well as Drp1, Mfn1, and OPA1 controlling mitochondrial dynamics in the substantia nigra (SN). Nrf2 KO aggravated the defects above in SN of aged male mice. Testosterone supplementation to WT-aged male mice significantly ameliorated mitochondrial function and upregulated mitochondrial biogenesis and mitochondrial dynamics, which were not shown in Nrf2 KO-aged male mice due to Nrf2 deficiency. Testosterone deficiency by gonadectomy (GDX) decreased mitochondrial function, downregulated mitochondrial biogenesis, and altered mitochondrial dynamics balance in young male mice. Supplementation with testosterone to Nrf2 KO-GDX mice only ameliorated the alterations above but did not reverse them to sham level. Nrf2 deficiency attenuated testosterone efficiency in ameliorating mitochondrial function in the SN of aged male mice through mitochondrial biogenesis and mitochondrial dynamics to some extent. Activation of Nrf2 might contribute to testosterone-upregulating mitochondrial biogenesis and mitochondrial dynamics in the SN during aging to produce efficient mitochondria for ATP production.
    DOI:  https://doi.org/10.1155/2022/3644318
  11. EMBO J. 2022 Mar 03. e109890
    Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.
    Heon-Woo Lee, Yanying Xu, Xiaolong Zhu, Cholsoon Jang, Woosung Choi, Hosung Bae, Weiwei Wang, Liqun He, Suk-Won Jin, Zoltan Arany, Michael Simons.
      Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte proximity is required to facilitate the transport of endothelium-derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter-1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood-brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood-brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.
    Keywords:  BBB permeability; Glucose; endothelial metabolism; lactate; pericyte metabolism
    DOI:  https://doi.org/10.15252/embj.2021109890
  12. Pharmacol Res. 2022 Feb 28. pii: S1043-6618(22)00094-9. [Epub ahead of print] 106149
    Therapeutic Induction of Energy Metabolism Reduces Neural Tissue Damage and Increases Microglia Activation in Severe Spinal Cord Injury.
    Sissi Dolci, Loris Mannino, Emanuela Bottani, Alessandra Campanelli, Marzia Di Chio, Stefania Zorzin, Giulia D'Arrigo, Alessia Amenta, Agnese Segala, Giuseppe Paglia, Vanna Denti, Guido Fumagalli, Enzo Nisoli, Alessandra Valerio, Claudia Verderio, Giuseppe Martano, Francesco Bifari, Ilaria Decimo.
      Neural tissue has high metabolic requirements. Following spinal cord injury (SCI), the damaged, tissue suffers from a severe metabolic impairment, which aggravates axonal degeneration and, neuronal loss. Impaired cellular energetic, tricarboxylic acid (TCA) cycle and oxidative, phosphorylation metabolism in neuronal cells has been demonstrated to be a major cause of neural tissue death and regeneration failure following SCI. Therefore, rewiring the spinal cord cell metabolism may be an innovative therapeutic strategy for the treatment of SCI. In this study, we evaluated the therapeutic effect of the recovery of oxidative metabolism in a mouse model of severe contusive SCI. Oral administration of TCA cycle intermediates, co-factors, essential amino acids, and branched-chain amino acids was started 3 days post-injury and continued until the end of the experimental procedures. Metabolomic, immunohistological, and biochemical analyses were performed on the injured spinal cord sections. Administration of metabolic precursors enhanced spinal cord oxidative metabolism. In line with this metabolic shift, we observed the activation of the mTORC1 anabolic pathway, the increase in mitochondrial mass, and ROS defense which effectively prevented the injury-induced neural cell apoptosis in treated animals. Consistently, we found more choline acetyltransferase (ChAT)-expressing motor neurons and increased neurofilament positive corticospinal axons in the spinal cord parenchyma of the treated mice. Interestingly, oral administration of the metabolic precursors increased the number of activated microglia expressing the CD206 marker suggestive of a, pro-resolutive, M2-like phenotype. These molecular and histological modifications observed in treated animals ultimately led to a significant, although partial, improvement of the motor functions. Our data demonstrate that rewiring the cellular metabolism can represent an effective strategy to treat SCI.
    Keywords:  Spinal cord injury; cell metabolism; microglia; mitochondrial metabolism; neural regeneration
    DOI:  https://doi.org/10.1016/j.phrs.2022.106149
  13. Front Aging Neurosci. 2021 ;13 798410
    The Effect of Aging on Brain Glucose Metabolic Connectivity Revealed by [18F]FDG PET-MR and Individual Brain Networks.
    Nathalie Mertens, Stefan Sunaert, Koen Van Laere, Michel Koole.
      Contrary to group-based brain connectivity analyses, the aim of this study was to construct individual brain metabolic networks to determine age-related effects on brain metabolic connectivity. Static 40-60 min [18F]FDG positron emission tomography (PET) images of 67 healthy subjects between 20 and 82 years were acquired with an integrated PET-MR system. Network nodes were defined by brain parcellation using the Schaefer atlas, while connectivity strength between two nodes was determined by comparing the distribution of PET uptake values within each node using a Kullback-Leibler divergence similarity estimation (KLSE). After constructing individual brain networks, a linear and quadratic regression analysis of metabolic connectivity strengths within- and between-networks was performed to model age-dependency. In addition, the age dependency of metrics for network integration (characteristic path length), segregation (clustering coefficient and local efficiency), and centrality (number of hubs) was assessed within the whole brain and within predefined functional subnetworks. Overall, a decrease of metabolic connectivity strength with healthy aging was found within the whole-brain network and several subnetworks except within the somatomotor, limbic, and visual network. The same decrease of metabolic connectivity was found between several networks across the whole-brain network and the functional subnetworks. In terms of network topology, a less integrated and less segregated network was observed with aging, while the distribution and the number of hubs did not change with aging, suggesting that brain metabolic networks are not reorganized during the adult lifespan. In conclusion, using an individual brain metabolic network approach, a decrease in metabolic connectivity strength was observed with healthy aging, both within the whole brain and within several predefined networks. These findings can be used in a diagnostic setting to differentiate between age-related changes in brain metabolic connectivity strength and changes caused by early development of neurodegeneration.
    Keywords:  [18F]FDG PET; functional connectivity; healthy aging; individual brain network; metabolic connectivity
    DOI:  https://doi.org/10.3389/fnagi.2021.798410
  14. Neurochem Res. 2022 Feb 28.
    Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains.
    Pulleri Kandi Harsha, Sathyanarayanan Ranganayaki, Gowri Yale, Gourav Dey, Kiran K Mangalaparthi, Anusha Yarlagadda, B K Chandrasekhar Sagar, Anita Mahadevan, M M Srinivas Bharath, Reeta S Mani.
      Rabies is a fatal encephalitis caused by the Rabies lyssavirus (RABV). The presence of minimal neuropathological changes observed in rabies indicates that neuronal dysfunction, rather than neuronal death contributes to the fatal outcome. The role of mitochondrial changes has been suggested as a possible mechanism for neuronal dysfunction in rabies. However, these findings are mostly based on studies that have employed experimental models and laboratory-adapted virus. Studies on brain tissues from naturally infected human and animal hosts are lacking. The current study investigated the role of mitochondrial changes in rabies by morphological, biochemical and proteomic analysis of RABV-infected human and canine brains. Morphological analysis showed minimal inflammation with preserved neuronal and disrupted mitochondrial structure in both human and canine brains. Proteomic analysis revealed involvement of mitochondrial processes (oxidative phosphorylation, cristae formation, homeostasis and transport), synaptic proteins and autophagic pathways, with over-expression of subunits of mitochondrial respiratory complexes. Consistent with these findings, human and canine brains displayed elevated activities of complexes I (p < 0.05), IV (p < 0.05) and V (p < 0.05). However, this did not result in elevated ATP production (p < 0.0001), probably due to lowered mitochondrial membrane potential as noted in RABV-infected cells in culture. These could lead to mitochondrial dysfunction and mitophagy as indicated by expression of FKBP8 (p < 0.05) and PINK1 (p < 0.001)/PARKIN (p > 0.05) and ensuing autophagy, as shown by the status of LCIII (p < 0.05), LAMP1 (p < 0.001) and pertinent ultrastructural markers. We propose that altered mitochondrial bioenergetics and cristae architecture probably induce mitophagy, leading to autophagy and consequent neuronal dysfunction in rabies.
    Keywords:  Mitochondria; Neuronal dysfunction; Proteomics; Rabies
    DOI:  https://doi.org/10.1007/s11064-022-03556-6
  15. Brain. 2022 Mar 02. pii: awac084. [Epub ahead of print]
    Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.
    Han Soo Yoo, Seong Ho Jeong, Kyeong Taek Oh, Sangwon Lee, Young H Sohn, Byoung Seok Ye, Mijin Yun, Phil Hyu Lee.
      Dementia with Lewy bodies, the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behavior disorder, and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism, and cognition in dementia with Lewy bodies. We enrolled 55 patients with probable dementia with Lewy bodies (15 prodromal dementia with Lewy bodies and 40 dementia with Lewy bodies) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography/computed tomography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography, 18F-florbetaben positron emission tomography/computed tomography, and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed by general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake, and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the dementia with Lewy bodies-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall, and Controlled Oral Word Association Test Animal. Path analyses showed that the effect of reduced caudate dopamine on Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with COWAT animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in dementia with Lewy bodies, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.
    Keywords:  brain metabolism; cognition; dementia with Lewy bodies; dopamine transporter
    DOI:  https://doi.org/10.1093/brain/awac084
  16. Mol Neurobiol. 2022 Mar 01.
    Ginsenoside Rg1 Reduced Microglial Activation and Mitochondrial Dysfunction to Alleviate Depression-Like Behaviour Via the GAS5/EZH2/SOCS3/NRF2 Axis.
    Junnan Li, Wei Gao, Zhonghui Zhao, Yannan Li, Lixuan Yang, Wei Wei, Feifei Ren, Yang Li, Yao Yu, Wenzhe Duan, Jingchun Li, Baoan Dai, Rongjuan Guo.
      Ginsenoside Rg1 is the principal active ingredient in ginseng. The antidepressant effects of Rg1 have been validated; however, the specific underlying mechanism of this effect needs further research. Rats were subjected to the chronic restraint stress (CRS) depression model. Rg1, or a positive control drug, was administered to the rats. Depression-like behaviours were evaluated through behavioural experiments. Cytokine, mRNA, protein, ATP, and mitochondria DNA levels were detected using the indicated methods. Lentivirus-packaged plasmids were injected into the rat brain for GAS5 overexpression or knockdown. In vitro mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species and mitochondrial membrane potential. Direct interaction between GAS5 and EZH2 was validated by RNA immunoprecipitation and RNA pull-down assay. The enrichment of EZH2 and H3K27me3 was evaluated through chromatin immunoprecipitation quantitative real-time PCR. Rg1 treatment alleviated depression-like behaviours, microglial activation, and mitochondrial dysfunction in CRS rats. Similarly, GAS5 knockdown revealed a similar protective effect of Rg1 treatment. GAS5 overexpression in the rat brain compromised the protective effect of Rg1 treatment. Moreover, Rg1 treatment or GAS5 knockdown attenuated microglial activation and mitochondrial dysfunction in vitro. Mechanically, GAS5 was suppressed SOCS3 and NRF2 expression by facilitating EZH2-mediated transcriptional repression. Rg1 attenuated microglial activation and improved mitochondrial dysfunction in depression by downregulating GAS5 expression. Mechanically, GAS5 might regulate microglial activation and mitochondrial dysfunction via the epigenetic suppression of NRF2 and SOCS3.
    Keywords:  Depression; EZH2; GAS5; Ginsenoside Rg1; NRF2; SOCS3
    DOI:  https://doi.org/10.1007/s12035-022-02740-7
  17. Front Aging Neurosci. 2022 ;14 772066
    Hippocampus-Based Mitochondrial Respiratory Function Decline Is Responsible for Perioperative Neurocognitive Disorders.
    Keqiang He, Juan Zhang, Wei Zhang, Sheng Wang, Dingfeng Li, Xiaolin Ma, Xiaofan Wu, Xiaoqing Chai, Qiang Liu.
      Perioperative neurocognitive disorders (PNDs) are a type of cognitive dysfunction occurring with a higher incidence in elderly patients. However, the pathological mechanism of PND and effective treatment remain elusive. We generated a PND mouse model by providing wild-type mice with surgical trauma; in our case, we used tibial fracture to investigate PND pathology. Mice aged 7-8 months were randomly divided into two groups: the surgery (tibial fracture) group and the control (sham) group. All mice were subjected to anesthesia. We examined the transcriptome-wide response in the hippocampus, a brain region that is tightly associated with memory formation, of control mice and mice subjected to surgical trauma at day 1 and day 3 after the surgical procedure. We observed reduced transcript levels of respiratory complex components as early as day 1 after surgery, and subsequent protein changes were found at day 3 after surgical trauma. Consequently, the activities of respiratory complexes were reduced, and adenosine triphosphate (ATP) production was decreased in the hippocampus of mice with surgical operations, supporting that respiratory chain function was impaired. In support of these conclusions, the mitochondrial membrane potential (MMP) levels were decreased, and the reactive oxygen species (ROS) levels were significantly increased. Mechanistically, we demonstrated that surgery induced a significant increase in cytokine IL-1β levels at day 1 after surgery, which concomitantly occurred with transcript changes in respiratory complex components. We further uncovered that transcription factors PGC-1α and NRF-1 were responsible for the observed transcript changes in mitochondrial complex components. Importantly, HT22 cells treated with the cytokine IL-1β resulted in similar reductions in PGC-1α and NRF-1, leading to a reduction of both the transcript and protein levels of respiratory complex subunits. Consequently, respiratory function was impaired in HT22 cells treated with IL-1β. Taken together, we demonstrated that reductions in respiratory complex components and subsequent impairment in mitochondrial functions serve as a novel mechanism for PND pathology, providing a potential therapeutic target for PND treatment.
    Keywords:  mitochondrial respiratory chain complex; neuroinflammation; perioperative neurocognitive disorders; postoperative cognitive dysfunction; respiratory function
    DOI:  https://doi.org/10.3389/fnagi.2022.772066
  18. J Cereb Blood Flow Metab. 2022 Mar 03. 271678X221080324
    Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.
    Marc Briquet, Anne-Bérengère Rocher, Maxime Alessandri, Nadia Rosenberg, Haissa de Castro Abrantes, Joel Wellbourne-Wood, Céline Schmuziger, Vanessa Ginet, Julien Puyal, Etienne Pralong, Roy Thomas Daniel, Stefan Offermanns, Jean-Yves Chatton.
      Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.
    Keywords:  Dentate gyrus; HCA1 receptor; electrophysiology; epilepsy; human brain slices
    DOI:  https://doi.org/10.1177/0271678X221080324
  19. Front Aging Neurosci. 2022 ;14 809767
    Gender-Related Differences in Regional Cerebral Glucose Metabolism in Normal Aging Brain.
    Bei Feng, Jiang Cao, YaPing Yu, HaiYan Yang, YangHongYan Jiang, Ying Liu, Rong Wang, Qian Zhao.
      Objectives: This study was aimed to investigate the gender-related differences of regional cerebral glucose metabolism in healthy people along the age using 18F-FDG PET/CT. Methods: We recruited 344 healthy volunteers, including 217 males and 127 females (age range: 40-89 years old). All subjects underwent fluorine-18 fluorodeoxyglucose(18F-FDG) positron emission tomography (PET). All the data were divided into four groups for every 10 years old. Each participant was carefully screened from PET, MR, and other examinations in order to exclude the abnormalities, such as neurodegenerative or psychiatric disorders, alcohol/abuse, cerebral vascular disorders, metabolic diseases like diabetes mellitus and hyperthyroidism, and other systemic malignancies. The 40-50 years old group was set as the baseline group. Statistical parametric mapping (SPM) analysis was employed to illustrate the differences among groups. Results: Compared to the baseline group, whether in a cohort or different gender groups, the decrease of brain glucose metabolism was shown in the bilateral frontal lobe, anterior cingulate gyrus, and the bilateral temporal lobe. In males, the regions of decreased metabolism were bilateral frontal lobe, caudate nucleus, and cingulate gyrus, whereas that of females were left occipital lobe, cerebellum, and the thalamus. However, the overall decrease of brain metabolism in men and women began from the age of 60s, an aggravated decrease from 70s was only observed in males. Conclusion: (1) An obviously decreased brain metabolism was found from 60 years old, especially in the bilateral frontal lobe, bilateral temporal lobe, and inferior cingulate gyrus; (2) We found specific brain metabolic differences between genders, including the caudate nucleus region in males and the occipital lobe region in females; and (3) The aging trend is different between genders.
    Keywords:  18F-FDG; PET; SPM; aging brain; gender differences
    DOI:  https://doi.org/10.3389/fnagi.2022.809767
  20. J Am Heart Assoc. 2022 Mar 01. e022107
    Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle-Aged Adults.
    Rebecca Angoff, Jayandra J Himali, Pauline Maillard, Hugo J Aparicio, Ramachandran S Vasan, Sudha Seshadri, Alexa S Beiser, Connie W Tsao.
      Background We aimed to evaluate the association between metabolic health and obesity and brain health measured via magnetic resonance imaging and neurocognitive testing in community dwelling adults. Methods and Results Framingham Heart Study Third Generation Cohort members (n=2170, 46±9 years of age, 54% women) without prevalent diabetes, stroke, dementia, or other neurologic conditions were grouped by metabolic unhealthiness (≥2 criteria for metabolic syndrome) and obesity (body mass index ≥30 kg/m2): metabolically healthy (MH) nonobese, MH obese, metabolically unhealthy (MU) nonobese, and MU obese. We evaluated the relationships of these groups with brain structure (magnetic resonance imaging) and function (neurocognitive tests). In multivariable-adjusted analyses, metabolically unhealthy individuals (MU nonobese and MU obese) had lower total cerebral brain volume compared with the MH nonobese referent group (both P<0.05). Additionally, the MU obese group had greater white matter hyperintensity volume (P=0.004), whereas no association was noted between white matter hyperintensity volume and either groups of metabolic health or obesity alone. Obese individuals had less favorable cognitive scores: MH obese had lower scores on global cognition, Logical Memory-Delayed Recall and Similarities tests, and MU obese had lower scores on Similarities and Visual Reproductions-Delayed tests (all P≤0.04). MU and obese groups had higher free water content and lower fractional anisotropy in several brain regions, consistent with loss of white matter integrity. Conclusions In this cross-sectional cohort study of younger to middle-aged adults, poor metabolic health and obesity were associated with structural and functional evidence of brain aging. Improvement in metabolic health and obesity may present opportunities to improve long-term brain health.
    Keywords:  aging; cognitive aging; magnetic resonance imaging; metabolic syndrome; obesity
    DOI:  https://doi.org/10.1161/JAHA.121.022107
  21. Front Nutr. 2022 ;9 823893
    A Nutrient Formulation Affects Developmental Myelination in Term Infants: A Randomized Clinical Trial.
    Nora Schneider, Muriel M K Bruchhage, Barry V O'Neill, Mickaël Hartweg, Jérôme Tanguy, Pascal Steiner, Gisella Mutungi, Jonathan O'Regan, Séamus Mcsweeney, Viren D'Sa, Sean C L Deoni.
       Background and Objectives: Observational studies suggest differences between breast-fed and formula-fed infants in developmental myelination, a key brain process for learning. The study aims to investigate the efficacy of a blend of docosahexaenoic acid (DHA), arachidonic acid (ARA), iron, vitamin B12, folic acid, and sphingomyelin (SM) from a uniquely processed whey protein concentrate enriched in alpha-lactalbumin and phospholipids compared with a control formulation on myelination, cognitive, and behavioral development in the first 6 months of life.
    Methods: These are 6-month results from an ongoing two-center, randomized controlled trial with a 12-month intervention period (completed for all participants). In this study, full term, neurotypical infants of both sexes (N = 81) were randomized into investigational (N = 42) or control groups (N = 39). In addition, non-randomized breast-fed children (N = 108) serve as a natural reference group. Main outcomes are myelination (MRI), cognitive (Bayley Scales of Infant and Toddler Development, 3rd edition [Bayley-III]), social-emotional development (Ages and Stages Questionnaires: Social-Emotional, 2nd edition [ASQ:SE-2]), sleep (Brief Infant Sleep Questionnaire [BISQ]), and safety (growth and adverse events [AEs]).
    Results: The full analyses set comprises N = 66 infants. Significant differences in myelin structure, volume, and rate of myelination were observed in favor of the investigational myelin blend at 3 and 6 months of life. Effects were demonstrated for whole brain myelin and for cerebellar, parietal, occipital, and temporal regions, known to be functionally involved in sensory, motor, and language skills. No statistically significant differences were found for early behavior and cognition scores.
    Conclusions: This is the first study demonstrating the efficacy of a myelin nutrient blend in well-nourished, term infants on developmental myelination, which may be foundational for later cognitive and learning outcomes.
    Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03111927.
    Keywords:  MRI; brain development; infant nutrition; myelination; phospholipids
    DOI:  https://doi.org/10.3389/fnut.2022.823893
  22. Neuroscience. 2022 Feb 26. pii: S0306-4522(22)00083-5. [Epub ahead of print]
    Corrigendum to: De novo Lipogenesis in Astrocytes Promotes the Repair of Blood-Brain Barrier after Transient Cerebral Ischemia Through Interleukin-33 [Neuroscience 481 (2022) 85-98].
    Haidong Wei, Luming Zhen, Shiquan Wang, Yuanyuan Zhang, Kui Wang, Pengyu Jia, Yan Zhang, Zhixin Wu, Qianzi Yang, Wugang Hou, Jianrui Lv, Pengbo Zhang.
      
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.02.020
  23. Biochem Biophys Res Commun. 2022 Jan 31. pii: S0006-291X(22)00152-8. [Epub ahead of print]601 101-108
    Shielded geomagnetic field accelerates glucose consumption in human neuroblastoma cells by promoting anaerobic glycolysis.
    Guo-Mi Wang, Jing-Peng Fu, Wei-Chuan Mo, Hai-Tao Zhang, Ying Liu, Rong-Qiao He.
      A shielded geomagnetic field, also called the hypomagnetic field (HMF), interferes with the metabolic processes of various cells and animals exhibiting diverse effects in different models, however, its underlying mechanism remains largely unknown. In this study, we assessed the effect on the energy metabolism of SH-SY5Y cells in HMF and found that HMF-induced cell proliferation depends on glucose supply. HMF promoted SH-SY5Y cell proliferation by increasing glucose consumption rate via up-regulating anaerobic glycolysis in the cells. Increased activity of LDH, a key member of glycolysis, was possibly a direct response to HMF-induced cell proliferation. Thus, we unveiled a novel subcellular mechanism underlying the HMF-induced cellular response: the up-regulation of anaerobic glycolysis and repression of oxidative stress shifted cellular metabolism more towards the Warburg effect commonly observed in cancer metabolism. We suggest that cellular metabolic profiles of various cell types may determine HMF-induced cellular effects, and a magnetic field can be applied as a non-invasive regulator of cell metabolism.
    Keywords:  Cell metabolism; Cell proliferation; Glycolysis; Hypomagnetic field
    DOI:  https://doi.org/10.1016/j.bbrc.2022.01.114
  24. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00162-0. [Epub ahead of print]38(9): 110435
    Isoform- and cell-state-specific lipidation of ApoE in astrocytes.
    Karina Lindner, Katharina Beckenbauer, Larissa C van Ek, Kevin Titeca, Sherida M de Leeuw, Khader Awwad, Franziska Hanke, Alla V Korepanova, Vladimir Rybin, Elizabeth Louise van der Kam, Eric G Mohler, Christian Tackenberg, Viktor Lakics, Anne-Claude Gavin.
      Apolipoprotein E transports lipids and couples metabolism between astrocytes and neurons. The E4 variant (APOE4) affects these functions and represents a genetic predisposition for Alzheimer's disease, but the molecular mechanisms remain elusive. We show that ApoE produces different types of lipoproteins via distinct lipidation pathways. ApoE forms high-density lipoprotein (HDL)-like, cholesterol-rich particles via the ATP-binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress-associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol-rich lipoproteins, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10-20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. We propose that fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion.
    Keywords:  ABCA1; Alzheimer's disease; iPSC-derived astrocyte; lipid droplet; lipid metabolism; lipid transport; lipid-binding; lipidomics; lipoprotein; triacylglycerol
    DOI:  https://doi.org/10.1016/j.celrep.2022.110435
  25. Anal Biochem. 2022 Feb 25. pii: S0003-2697(22)00063-X. [Epub ahead of print] 114607
    Time-dependent influence of high glucose environment on the metabolism of neuronal immortalized cells.
    Laura Colombaioni, Beatrice Campanella, Riccardo Nieri, Massimo Onor, Edoardo Benedetti, Emilia Bramanti.
      Mitochondria are organelles of bacterial origin historically identified as the cell power plant. In addition to energy, mitochondria produce reactive oxygen species and they have been found to have a key role in cell defense regulation, cell stress and damage. All the investigations regarding the nature of the molecules mediating these processes include compounds from mammalian cell metabolism. We hypothesize that the bacterial origin of mitochondria brings them to produce small fermentation products when cell is subjected to stress. In this work we studied the effect of hyperglycemia on the metabolome of hippocampal HN9.10e neurons, an in vitro model of one of the most vulnerable regions of central nervous system. Targeted metabolites were analyzed in the cell culture medium by liquid chromatography - diode array detection and headspace - gas chromatography - mass spectrometry. Twenty-two low molecular weight metabolites were identified and quantified in the growth medium of the cells, treated with 25, 50 or 75 mM glucose, sampled along 8 days to mimic a prolonged hyperglycemia. The results of statistical analysis showed the clear impairment of neuronal metabolism already after 48 h, represented by a significant reduction of the metabolic activity, together with the production of typical fermentative compounds.
    Keywords:  3-Way PCA; Cell death; HPLC-DAD; Hyperglycemia; Primary cultured hippocampal neurons; Targeted metabolomics
    DOI:  https://doi.org/10.1016/j.ab.2022.114607
  26. Front Mol Neurosci. 2022 ;15 812479
    The Impact of Electroacupuncture Early Intervention on the Brain Lipidome in a Mouse Model of Post-traumatic Stress Disorder.
    Cui-Hong Zhou, Fen Xue, Qing-Qing Shi, Shan-Shan Xue, Tian Zhang, Xin-Xu Ma, Li-Sheng Yu, Chuang Liu, Hua-Ning Wang, Zheng-Wu Peng.
      The neuroprotective effect of electroacupuncture (EA) treatment has been well studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of post-traumatic stress disorder (PTSD) and may be a target for treatment. However, the influence of early EA intervention on brain lipid composition in patients with PTSD has never been investigated. Using a modified single prolonged stress (mSPS) model in mice, we assessed the anti-PTSD-like effects of early intervention using EA and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. mSPS induced changes in lipid composition in the hippocampus, notably in the content of sphingolipids, glycerolipids, and fatty acyls. These lipid changes were more robust than those observed in the PFC. Early intervention with EA after mSPS ameliorated PTSD-like behaviors and partly normalized mSPS-induced lipid changes, notably in the hippocampus. Cumulatively, our data suggest that EA may reverse mSPS-induced PTSD-like behaviors due to region-specific regulation of the brain lipidome, providing new insights into the therapeutic mechanism of EA.
    Keywords:  electroacupuncture; hippocampus; lipidomics; mouse model; post-traumatic stress disorder; prefrontal cortex
    DOI:  https://doi.org/10.3389/fnmol.2022.812479
  27. Auton Neurosci. 2022 Feb 22. pii: S1566-0702(22)00016-9. [Epub ahead of print]239 102957
    Glucose infusion suppresses acute restraint stress-induced peripheral and central sympathetic responses in rats.
    Naoko Yamaguchi, Yoshihiko Kakinuma, Tomiko Yakura, Munekazu Naito, Shoshiro Okada.
       BACKGROUND: Acute restraint stress (RS) induces sympathetic activation such as elevating plasma catecholamines, resulting in increase in blood glucose. We aimed to investigate whether glucose infusion affects the RS-induced sympathetic responses.
    METHODS: Plasma catecholamines were measured by high-performance liquid chromatography with electrochemical detection. Blood glucose levels were measured with a glucometer and a glucose assay kit. Cardiac parameters were measured by echocardiographic and hemodynamic analysis. Prostanoid levels in the paraventricular nucleus of hypothalamus (PVN) microdialysates were measured by liquid chromatography-ion trap tandem mass spectrometry analysis.
    RESULTS: RS significantly increased plasma noradrenaline and adrenaline. Intravenous infusion of a 5% glucose solution significantly attenuated the RS-induced elevation of plasma adrenaline but did not alter the plasma noradrenaline. Glucose administration during RS suppressed the progression of cardiac impairment by attenuating the decline rates in left ventricular diastolic, end-diastolic volume, stroke volume, fractional shortening, and ejection fraction. Both Intravenous and intracerebroventricular infusion of glucose solution significantly attenuated the RS-induced elevation of thromboxane B2 (TxB2) (a metabolite of TxA2) levels in the PVN but did not alter prostaglandin E2 levels in the PVN.
    CONCLUSION: Our results demonstrate that glucose infusion suppresses RS-induced elevation of plasma adrenaline and left ventricular dysfunction. In the brain, glucose infusion suppresses RS-induced production of TxA2 in the PVN.
    Keywords:  Paraventricular nucleus of hypothalamus; Plasma catecholamines; Prostanoids; Restraint stress; Takotsubo cardiomyopathy
    DOI:  https://doi.org/10.1016/j.autneu.2022.102957
  28. Neurotoxicology. 2022 Feb 24. pii: S0161-813X(22)00024-9. [Epub ahead of print]90 35-47
    Glycolytic and Krebs cycle enzymes activity in rat prefrontal cortex, hippocampus, and striatum after single and repeated NMDA inhibition by MK-801.
    David Kolar, Lenka Kleteckova, Katerina Skalova, Hana Brozka, Martin Kalous, Karel Vales.
      Psychosis is a state of altered thoughts which often accompanies schizophrenia. It was suggested that changes in energetic metabolism accompany psychosis and post-psychosis states. Here, we use the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to experimentally induce psychosis-like behavior in rats. We addressed an effect of single and repeated (5×) MK-801 application (0.3 mg/kg; i.p.) on the energy metabolism in homogenates and crude mitochondrial fraction (CMF) of the striatum (STR), prefrontal cortex (PFC), and the hippocampus (HIP) of the adult male Wistar rat (n = 39). In each brain region, we assessed activity of glycolytic (hexokinase (HK) and lactate dehydrogenase (LDH)) and Krebs cycle enzymes (citrate synthase (CS) and malate dehydrogenase (MDH)) 2 h and 3 days (3d) after the last MK-801 application together with relative respiratory rates assessment in tissue homogenate. In STR, a single MK-801 application led to a decrease in the LDH (p = 0.0035) and the increase of the MDH (p = 0.0043) activities following 3d. Therein, repeated MK-801 doses evoked increased LDH (p = 0.0204) and CS (p = 0.0019) activities in the homogenate 2 h and increased HK (p = 0.0007) 3d after the last application. Elevated HK activity within CMF was observed after 3d (p = 0.0054). In PFC, repeated MK-801 application decreased HK activity in the homogenate 3d after the final application (p = 0.0234). Correspondingly, PFC HK activity in CMF of repeated administration samples dropped (p = 0.003). In HIP, repeated MK-801 administration led to increased respiration of SDH (p = 0.0475) only 2 h after the last application and decreased CS activity (p = 0.0160) was observed 3d after the last application. Our results indicate a progressive metabolic dysregulation of glycolytic and Krebs cycle enzymes following repeated inhibition of NMDA receptors activity in a region-specific manner. Energetic alterations may form a basis for persisting cognitive problems during and following a psychosis in schizophrenia patients.
    Keywords:  Citrate synthase; Energy metabolism; Hexokinase; Lactate dehydrogenase; Malate dehydrogenase; Schizophrenia
    DOI:  https://doi.org/10.1016/j.neuro.2022.02.005
  29. Life Sci. 2022 Mar 01. pii: S0024-3205(22)00146-1. [Epub ahead of print] 120446
    Ceramide kinase knockout ameliorates multiple sclerosis-like behaviors and demyelination in cuprizone-treated mice.
    Ai Tanaka, Kohei Anada, Masataka Yasue, Takuya Honda, Hiroyuki Nakamura, Toshihiko Murayama.
      Changes in sphingolipid metabolism regulate and/or alter many cellular functions in the brain. Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). CerK and C1P were reported to regulate many cellular responses, but their roles in immune-related diseases in vivo have not been well elucidated. Thus, we investigated the effects of CerK knockout on the onset/progression of multiple sclerosis (MS), which is a chronic neurodegenerative disease accompanied by the loss of myelin sheaths in the brain. MS-model mice were prepared using a diet containing the copper chelator cuprizone (CPZ). Treatment of 8-week-old mice with 0.2% CPZ for 8 weeks resulted in motor dysfunction based on the Rota-rod test, and caused the loss of myelin-related proteins (MRPs) in the brain and demyelination in the corpus callosum without affecting synaptophysin levels. CerK knockout, which did not affect developmental changes in MRPs, ameliorated the motor dysfunction, loss of MRPs, and demyelination in the brain in CPZ-treated mice. Loss of tail tonus, another marker of motor dysfunction, was detected at 1 week without demyelination after CPZ treatment in a CerK knockout-independent manner. CPZ-induced loss of tail tonus progressed, specifically in female mice, to 6-8 weeks, and the loss was ameliorated by CerK knockout. Activities of ceramide metabolic enzymes including CerK in the lysates of the brain were not affected by CPZ treatment. Inhibition of CerK as a candidate for MS treatment was discussed.
    Keywords:  Ceramide-1-phosphate; Gender; Inflammation; Motor dysfunction; Neutrophils; Oligodendrocyte
    DOI:  https://doi.org/10.1016/j.lfs.2022.120446
  30. Neuroradiology. 2022 Feb 28.
    Clinical 1H MRS in childhood neurometabolic diseases - part 2: MRS signatures.
    Matthew T Whitehead, Lillian M Lai, Stefan Blüml.
      Proton MRS of the brain provides the ability to gather direct information regarding the metabolic status of the brain at the time of MRI. Although selective vulnerability of brain tissue may yield distinct imaging patterns in neurometabolic disorders, it is not uncommon for the brain MRI to be normal, nonspecific, or show ambiguous abnormalities among several possible diagnoses, metabolic, or otherwise. This review highlights childhood neurometabolic diseases in which 1H MRS may show diagnostic or suggestive metabolic profiles without complicated acquisition or postprocessing techniques.
    Keywords:  MRS; Metabolic; Metabolism; Spectroscopy
    DOI:  https://doi.org/10.1007/s00234-022-02918-9
  31. Metab Brain Dis. 2022 Mar 03.
    Protective effect of curcumin against rotenone-induced substantia nigra pars compacta neuronal dysfunction.
    L V Darbinyan, K V Simonyan, L E Hambardzumyan, L P Manukyan, S H Badalyan, V H Sarkisian.
      Rotenone is involved in the degeneration of dopaminergic neurons, and curcumin may prevent or effectively slow the progression of Parkinson's disease (PD). Previous research has shown that the naturally occurring phenolic compound curcumin can reduce inflammation and oxidation, making it a potential therapeutic agent for neurodegenerative diseases. The present study involves investigation of rotenone-induced histological changes in the brain area, hippocampus using Nissl staining after 35 day of subcutaneous injection of rotenone in adult male rats. We sought to determine whether curcumin could protect against rotenone-induced dopaminergic neurotoxicity in a rat model by in vivo electrical recording from Substantia nigra pars compacta (SNc). Curcumin treatment significantly improved electrical activity of neurons in the SNc of rotenone-induced PD model rats. The pattern of histological alterations corresponds with electrophysiological manifestations.
    Keywords:  Curcumin; In vivo electrophysiology; Rotenone; Substantia nigra pars compacta
    DOI:  https://doi.org/10.1007/s11011-022-00941-6
  32. Brain. 2022 Mar 04. pii: awab303. [Epub ahead of print]
    CLPP deficiency ameliorates neurodegeneration caused by impaired mitochondrial protein synthesis.
    Anastasia Rumyantseva, Milica Popovic, Aleksandra Trifunovic.
      Mitochondria are essential organelles found in every eukaryotic cell, required to convert food into usable energy. Therefore, it is not surprising that mutations in either mtDNA or nuclear DNA-encoded genes of mitochondrial proteins cause diseases affecting the oxidative phosphorylation system, which are heterogeneous from a clinical, genetic, biochemical and molecular perspective and can affect patients at any age. Despite all this, it is surprising that our understanding of the mechanisms governing mitochondrial gene expression and its associated pathologies remain superficial and therapeutic interventions largely unexplored. We recently showed that loss of the mitochondrial matrix protease caseinolytic protease proteolytic subunit (CLPP) ameliorates phenotypes in cells characterized by defects in oxidative phosphorylation maintenance. Here, we build upon this finding by showing that CLPP depletion is indeed beneficial in vivo for various types of neuronal populations, including Purkinje cells in the cerebellum and cortical and hippocampal neurons in the forebrain, as it strongly improves distinct phenotypes of mitochondria encephalopathy, driven by the deficiency of the mitochondrial aspartyl tRNA synthase DARS2. In the absence of CLPP, neurodegeneration of DARS2-deficient neurons is delayed as they present milder oxidative phosphorylation dysfunction. This in turn leads to a decreased neuroinflammatory response and significantly improved motor functions in both double-deficient models (Purkinje cell-specific or forebrain neuron-specific Dars2/Clpp double knockout mice). We propose that diminished turnover of respiratory complex I caused by the loss of CLPP is behind the improved phenotype in Dars2/Clpp double knockout animals, even though this intervention might not restore respiratory complex I activity but rather improve mitochondrial cristae morphology or help maintain the NAD+/NADH ratio inside mitochondria. These results also open the possibility of targeting CLPP activity in many other mitochondrial encephalopathies characterized by respiratory complex I instability.
    Keywords:  CLPP protease; DARS2 deficiency; LBSL; mitochondrial diseases
    DOI:  https://doi.org/10.1093/brain/awab303
  33. Front Neurosci. 2022 ;16 832478
    Blood Glutamate Scavenging With Pyruvate as a Novel Preventative and Therapeutic Approach for Depressive-Like Behavior Following Traumatic Brain Injury in a Rat Model.
    Dmitry Frank, Benjamin F Gruenbaum, Ilan Shelef, Vladislav Zvenigorodsky, Olena Severynovska, Ron Gal, Michael Dubilet, Alexander Zlotnik, Ora Kofman, Matthew Boyko.
      Depression is a common and serious complication following traumatic brain injury (TBI). Both depression and TBI have independently been associated with pathologically elevated extracellular brain glutamate levels. In the setting of TBI, blood glutamate scavenging with pyruvate has been widely shown as an effective method to provide neuroprotection by reducing blood glutamate and subsequent brain glutamate levels. Here we evaluate pyruvate as a novel approach in the treatment and prevention of post-TBI depression-like behavior in a rat model. Rats were divided into five groups: (1) sham-operated control with pyruvate, (2) sham-operated control with placebo, (3) post-TBI with placebo, (4) post-TBI given preventative pyruvate, and (5) post-TBI treated with pyruvate. These groups had an equal number of females and males. Rats were assessed for depressive-like behavior, neurological status, and glutamate levels in the blood and brain. Post-TBI neurological deficits with concurrent elevations in glutamate levels were demonstrated, with peak glutamate levels 24 h after TBI. Following TBI, the administration of either prophylactic or therapeutic pyruvate led to reduced glutamate levels, improved neurologic recovery, and improved depressive-like behavior. Glutamate scavenging with pyruvate may be an effective prophylactic and therapeutic option for post-TBI depression by reducing associated elevations in brain glutamate levels.
    Keywords:  depression; glutamate scavenging; neuroprotection; pyruvate; traumatic brain injury
    DOI:  https://doi.org/10.3389/fnins.2022.832478
  34. Neurotox Res. 2022 Mar 03.
    Quinolinic Acid Impairs Redox Homeostasis, Bioenergetic, and Cell Signaling in Rat Striatum Slices: Prevention by Coenzyme Q10.
    Fernanda Silva Ferreira, Tiago Marcon Dos Santos, Osmar Vieira Ramires Junior, Josiane Silva Silveira, Felipe Schmitz, Angela T S Wyse.
      Quinolinic acid (QUIN) is an important agonist of NMDA receptors that are found at high levels in cases of brain injury and neuroinflammation. Therefore, it is necessary to investigate neuroprotection strategies capable of neutralizing the effects of the QUIN on the brain. Coenzyme Q10 (CoQ10) is a provitamin that has an important antioxidant and anti-inflammatory action. This work aims to evaluate the possible neuroprotective effect of CoQ10 against the toxicity caused by QUIN. Striatal slices from 30-day-old Wistar rats were preincubated with CoQ10 25-100 μM for 15 min; then, QUIN 100 μM was added to the incubation medium for 30 min. A dose-response curve was used to select the CoQ10 concentration to be used in the study. Results showed that QUIN caused changes in the production of ROS, nitrite levels, activities of antioxidant enzymes, glutathione content, and damage to proteins and lipids. CoQ10 was able to prevent the effects caused by QUIN, totally or partially, except for damage to proteins. QUIN also altered the activities of electron transport chain complexes and ATP levels, and CoQ10 prevented totally and partially these effects, respectively. CoQ10 prevented the increase in acetylcholinesterase activity, but not the decrease in the activity of Na+,K+-ATPase caused by QUIN. We also observed that QUIN caused changes in the total ERK and phospho-Akt content, and these effects were partially prevented by CoQ10. These findings suggest that CoQ10 may be a promising therapeutic alternative for neuroprotection against QUIN neurotoxicity.
    Keywords:  Cell signaling; Coenzyme Q10; Energetic impairment; Neuroprotection; Quinolinic acid; Redox status
    DOI:  https://doi.org/10.1007/s12640-022-00484-9
  35. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00147-4. [Epub ahead of print]38(9): 110423
    Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord.
    Luipa Khandker, Marisa A Jeffries, Yun-Juan Chang, Marie L Mather, Angelina V Evangelou, Jennifer N Bourne, Azadeh K Tafreshi, Isis M Ornelas, Ozlem Bozdagi-Gunal, Wendy B Macklin, Teresa L Wood.
      Brain and spinal cord oligodendroglia have distinct functional characteristics, and cell-autonomous loss of individual genes can result in different regional phenotypes. However, a molecular basis for these distinctions is unknown. Using single-cell analysis of oligodendroglia during developmental myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis. We further identify the mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglia-specific loss of mTOR decreases cholesterol biosynthesis in both the brain and the spinal cord, but mTOR loss in spinal cord oligodendroglia has a greater impact on cholesterol biosynthesis, consistent with more pronounced deficits in developmental myelination. In the brain, mTOR loss results in a later adult myelin deficit, including oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain.
    Keywords:  cholesterol; mTOR; myelin; myelin maintenance; myelination; oligodendrocyte; oligodendrocyte heterogeneity; oligodendrocyte precursor; single-cell sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2022.110423
  36. Free Radic Biol Med. 2022 Feb 23. pii: S0891-5849(22)00075-2. [Epub ahead of print]
    Mineral requirements for mitochondrial function: A connection to redox balance and cellular differentiation.
    David W Killilea, Alison N Killilea.
      Professor Bruce Ames demonstrated that nutritional recommendations should be adjusted in order to 'tune-up' metabolism and reduce mitochondria decay, a hallmark of aging and many disease processes. A major subset of tunable nutrients are the minerals, which despite being integral to every aspect of metabolism are often deficient in the typical Western diet. Mitochondria are particularly rich in minerals, where they function as essential cofactors for mitochondrial physiology and overall cellular health. Yet substantial knowledge gaps remain in our understanding of the form and function of these minerals needed for metabolic harmony. Some of the minerals have known activities in the mitochondria but with incomplete regulatory detail, whereas other minerals have no established mitochondrial function at all. A comprehensive metallome of the mitochondria is needed to fully understand the patterns and relationships of minerals within metabolic processes and cellular development. This brief overview serves to highlight the current progress towards understanding mineral homeostasis in the mitochondria and to encourage more research activity in key areas. Future work may likely reveal that adjusting the amounts of specific nutritional minerals has longevity benefits for human health.
    Keywords:  Differentiation; Metals; Minerals; Mitochondria; Redox
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.022
  37. Phytother Res. 2022 Mar 02.
    Effects of alpha lipoic acid on metabolic syndrome: A comprehensive review.
    Nahid Najafi, Soghra Mehri, Mahboobeh Ghasemzadeh Rahbardar, Hossein Hosseinzadeh.
      Metabolic syndrome (MetS) is a multifactorial disease with medical conditions such as hypertension, diabetes, obesity, dyslipidemia, and insulin resistance. Alpha-lipoic acid (α-LA) possesses various pharmacological effects, including antidiabetic, antiobesity, hypotensive, and hypolipidemia actions. It exhibits reactive oxygen species scavenger properties against oxidation and age-related inflammation and refines MetS components. Also, α-LA activates the 5' adenosine monophosphate-activated protein kinase and inhibits the NFκb. It can decrease cholesterol biosynthesis, fatty acid β-oxidation, and vascular stiffness. α-LA decreases lipogenesis, cholesterol biosynthesis, low-density lipoprotein and very low-density lipoprotein levels, and atherosclerosis. Moreover, α-LA increases insulin secretion, glucose transport, and insulin sensitivity. These changes occur via PI3K/Akt activation. On the other hand, α-LA treats central obesity by increasing adiponectin levels and mitochondrial biogenesis and can reduce food intake mainly by SIRT1 stimulation. In this review, the most relevant articles have been discussed to determine the effects of α-LA on different components of MetS with a special focus on different molecular mechanisms behind these effects. This review exhibits the potential properties of α-LA in managing MetS; however, high-quality studies are needed to confirm the clinical efficacy of α-LA.
    Keywords:  alpha-lipoic acid; diabetes; dyslipidemia; hypertension; metabolic syndrome; obesity
    DOI:  https://doi.org/10.1002/ptr.7406
  38. Neurobiol Dis. 2022 Feb 24. pii: S0969-9961(22)00060-2. [Epub ahead of print]167 105669
    Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.
    Francisco Molinet-Dronda, Javier Blesa, Natalia López-González Del Rey, Carlos Juri, María Collantes, Jose A Pineda-Pardo, Inés Trigo-Damas, Elena Iglesias, Ledia F Hernández, Rafael Rodríguez-Rojas, Belén Gago, Margarita Ecay, Elena Prieto, Miguel Á García-Cabezas, Carmen Cavada, María C Rodríguez-Oroz, Iván Peñuelas, José A Obeso.
      Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.
    Keywords:  Glucose metabolism; Parkinson's disease; Positron emission tomography (PET); [(11)C]-dihydrotetrabenazine ((11)C-DTBZ); [(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG)
    DOI:  https://doi.org/10.1016/j.nbd.2022.105669
  39. Nutr Rev. 2022 Mar 04. pii: nuac015. [Epub ahead of print]
    Pregnancy-induced alterations of 1-carbon metabolism and significance for maternal nutrition requirements.
    Kelsey M Cochrane, Brock A Williams, Rajavel Elango, Susan I Barr, Crystal D Karakochuk.
       OBJECTIVES: The pregnancy-induced alterations in 1-carbon (1C) metabolism, effects of advancing gestation on maternal plasma concentrations of methyl nutrients, and potential implications for maternal dietary intake and infant clinical outcomes are summarized in this narrative review.
    BACKGROUND: 1C metabolism encompasses a series of pathways where 1C units are transferred among nutrients such as B vitamins, choline, and amino acids (the methyl nutrients). Use of isotopic tracers and measuring methyl nutrients in maternal plasma and infant cord blood has advanced the understanding of 1C flux in pregnancy and kinetics of maternal-placental-fetal transfer. Methyl nutrients are supplied from maternal plasma to the placenta and fetus to support growth and 1C metabolism in these compartments.
    METHODS: A literature review was completed in MEDLINE and Google Scholar using search terms related to 1C metabolism, methyl nutrients, and nutrition requirements in pregnancy. English-language articles were reviewed in which 1C metabolism in pregnancy, maternal-placental-fetal transfer of methyl nutrients, and determinants of maternal plasma concentrations of methyl nutrients among healthy pregnant women were assessed.
    DISCUSSION: Adaptations in 1C metabolism occur throughout a healthy pregnancy to support this unique period of accelerated growth. Studies report similar temporal changes in plasma concentrations of many methyl nutrients, including B vitamins, choline, betaine, methionine, and cysteine, among healthy pregnant women from diverse geographic regions. Other key findings discussed in this review include an apparent high degree of B vitamin transfer to the placenta and fetus, influence of choline supplementation on 1C flux and possible benefit of supplementation for infant cognitive development, and that glycine may be conditionally essential in pregnancy.
    CONCLUSION: Understanding the flux of 1C metabolism in pregnancy and methyl nutrient transfer from maternal plasma is needed to establish appropriate plasma references ranges and, ultimately, dietary recommendations that aim to prevent deficiency and associated adverse health outcomes for mother and baby.
    Keywords:  1-carbon metabolism; dietary recommendations; maternal nutrition; methyl nutrients; pregnancy
    DOI:  https://doi.org/10.1093/nutrit/nuac015
  40. Brain. 2022 Mar 04. pii: awac087. [Epub ahead of print]
    Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism.
    Leyre Merino-Galan, Haritz Jimenez-Urbieta, Marta Zamarbide, Tatiana Rodríguez-Chinchilla, Arantzazu Belloso-Iguerategui, Enrique Santamaria, Joaquín Fernández-Irigoyen, Ana Aiastui, Evelyne Doudnikoff, Erwan Bézard, Alberto Ouro, Shira Knafo, Belén Gago, Ana Quiroga-Varela, María Cruz Rodríguez-Oroz.
      Synaptic impairment might precede neuronal degeneration in Parkinson's disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding the symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53 T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. SWATH-MS proteomics identified deregulated proteins involved firstly in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics is followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolves. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated post-synaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells in order to delay or prevent the development of Parkinson's disease.
    Keywords:  Parkinson’s disease: synapse; mitochondria; striatum; α-synuclein
    DOI:  https://doi.org/10.1093/brain/awac087
  41. J Neurochem. 2022 Mar 02.
    Perturbation of monoamine metabolism and enhanced fear responses in mice defective in the regeneration of tetrahydrobiopterin.
    Katsuya Miyajima, Yusuke Sudo, Sho Sanechika, Yoshitaka Hara, Mieko Horiguchi, Feng Xu, Minori Suzuki, Satoshi Hara, Koichi Tanda, Ken-Ichi Inoue, Masahiko Takada, Nozomu Yoshioka, Hirohide Takebayashi, Masayo Mori-Kojima, Masahiro Sugimoto, Chiho Sumi-Ichinose, Kazunao Kondo, Keizo Takao, Tsuyoshi Miyakawa, Hiroshi Ichinose.
      Increasing evidence suggests the involvement of peripheral amino acid metabolism in the pathophysiology of neuropsychiatric disorders, whereas the molecular mechanisms are largely unknown. Tetrahydrobiopterin (BH4) is a cofactor for enzymes that catalyse phenylalanine metabolism, monoamine synthesis, nitric oxide production, and lipid metabolism. BH4 is synthesized from guanosine triphosphate and regenerated by quinonoid dihydropteridine reductase (QDPR), which catalyses the reduction in quinonoid dihydrobiopterin. We analysed Qdpr-/- mice to elucidate the physiological significance of the regeneration of BH4. We found that the Qdpr-/- mice exhibited mild hyperphenylalaninemia and monoamine deficiency in the brain, despite the presence of substantial amounts of BH4 in the liver and brain. Hyperphenylalaninemia was ameliorated by exogenously administered BH4, and dietary phenylalanine restriction was effective for restoring the decreased monoamine contents in the brain of the Qdpr-/- mice, suggesting that monoamine deficiency was caused by the secondary effect of hyperphenylalaninemia. Immunohistochemical analysis showed that QDPR was primarily distributed in oligodendrocytes but hardly detectable in monoaminergic neurons in the brain. Finally, we performed a behavioural assessment using a test battery. The Qdpr-/- mice exhibited enhanced fear responses after electrical foot shock. Taken together, our data suggest that the perturbation of BH4 metabolism should affect brain monoamine levels through alterations in peripheral amino acid metabolism, and might contribute to the development of anxiety-related psychiatric disorders.
    Keywords:  aromatic amino acid hydroxylases; hyperphenylalaninemia; monoamine neurotransmitters; oligodendrocytes; quinonoid dihydropteridine reductase; tetrahydrobiopterin
    DOI:  https://doi.org/10.1111/jnc.15600
  42. Sci Rep. 2022 Mar 04. 12(1): 3577
    Metabolomics and biochemical alterations caused by pleiotrophin in the 6-hydroxydopamine mouse model of Parkinson's disease.
    Esther Gramage, Jorge Sáiz, Rosalía Fernández-Calle, Yasmina B Martín, María Uribarri, Marcel Ferrer-Alcón, Coral Barbas, Gonzalo Herradón.
      Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival. PTN expression levels are upregulated in the nigrostriatal pathway of Parkinson's Disease (PD) patients. We aimed to characterize the dopaminergic injury and glial responses in the nigrostriatal pathway of mice with transgenic Ptn overexpression in the brain (Ptn-Tg) after intrastriatal injection of the catecholaminergic toxic 6-hydroxydopamine (6-OHDA) at a low dose (5 µg). Ten days after surgery, the injection of 6-OHDA induced a significant decrease of the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and of the striatal TH contents in Wild type (Wt) mice. In contrast, these effects of 6-OHDA were absent in Ptn-Tg mice. When the striatal Iba1 and GFAP immunoreactivity was studied, no statistical differences were found between vehicle-injected Wt and Ptn-Tg mice. Furthermore, 6-OHDA did not cause robust glial responses neither on Wt or Ptn-Tg mice 10 days after injections. In metabolomics studies, we detected interesting metabolites that significantly discriminate the more injured 6-OHDA-injected Wt striatum and the more protected 6-OHDA-injected Ptn-Tg striatum. Particularly, we detected groups of metabolites, mostly corresponding to phospholipids, whose trends were opposite in both groups. In summary, the data confirm lower 6-OHDA-induced decreases of TH contents in the nigrostriatal pathway of Ptn-Tg mice, suggesting a neuroprotective effect of brain PTN overexpression in this mouse model of PD. New lipid-related PD drug candidates emerge from this study and the data presented here support the increasingly recognized "lipid cascade" in PD.
    DOI:  https://doi.org/10.1038/s41598-022-07419-6
  43. J Neurosci. 2022 Feb 25. pii: JN-RM-1334-21. [Epub ahead of print]
    Disrupted choline clearance and sustained acetylcholine release in vivo by a common choline transporter coding variant associated with poor attentional control in humans.
    Eryn Donovan, Cassandra Avila, Sarah Klausner, Vinay Parikh, Cristina Fenollar-Ferrer, Randy D Blakely, Martin Sarter.
      Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, in vivo, CHT-mediated choline transport, and ACh release. Relative to wild type (WT) mice, CHT-mediated clearance of choline in male and female mice expressing one or two Val89 alleles was reduced by over 80% cortex and over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in total synaptosomal lysates and neuronal plasma-membrane-enriched fractions was not impacted by the Val89 variant, indicating a selective impact on CHT function. When challenged with a visual disruptor to reveal attentional control mechanisms, Val89 mice failed to adopt a more conservative response bias. Structural modeling revealed that Val89 may attenuate choline transport by altering conformational changes of CHT that support normal transport rates. Our findings support the view that diminished, sustained cholinergic signaling capacity underlies perturbed attentional performance in individuals expressing CHT Val89. The CHT Val89 mouse serves as a valuable model to study heritable risk for cognitive disorders arising from cholinergic dysfunction.SIGNIFICANCE STATEMENTAcetylcholine (ACh) signaling depends on the functional capacity of the neuronal choline transporter (CHT). Previous research demonstrated that humans expressing the common CHT coding variant Val89 exhibit attentional vulnerabilities and attenuated fronto-cortical activation during attention. Here, we find that mice engineered to express the Val89 variant exhibit reduced CHT-mediated choline clearance and a diminished capacity to sustain ACh release. Additionally, Val89 mice lack cognitive flexibility in response to an attentional challenge. These findings provide a mechanistic and cognitive framework for interpreting the attentional phenotype associated with the human Val89 variant and establish a model that permits a more invasive interrogation of CNS effects as well as the development of therapeutic strategies for those, including Val89 carriers, with presynaptic cholinergic perturbations.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1334-21.2022
  44. Aging Cell. 2022 Mar 02. e13576
    Drosophila Sirtuin 6 mediates developmental diet-dependent programming of adult physiology and survival.
    Namrata Shukla, Ullas Kolthur-Seetharam.
      Organisms in the wild experience unpredictable and diverse food availability throughout their lifespan. Over-/under-nutrition during development and in adulthood is known to dictate organismal survival and fitness. Studies using model systems have also established long-term effects of developmental dietary alterations on life-history traits. However, the underlining genetic/molecular factors, which differentially couple nutrient inputs during development with fitness later in life are far less understood. Using Drosophila and loss/gain of function perturbations, our serendipitous findings demonstrate an essential role of Sirtuin 6 in regulating larval developmental kinetics, in a nutrient-dependent manner. The absence of Sirt6 affected ecdysone and insulin signalling and led to accelerated larval development. Moreover, varying dietary glucose and yeast during larval stages resulted in enhanced susceptibility to metabolic and oxidative stress in adults. We also demonstrate an evolutionarily conserved role for Sirt6 in regulating physiological homeostasis, physical activity and organismal lifespan, known only in mammals until now. Our results highlight gene-diet interactions that dictate thresholding of nutrient inputs and physiological plasticity, operative across development and adulthood. In summary, besides showing its role in invertebrate ageing, our study also identifies Sirt6 as a key factor that programs macronutrient-dependent life-history traits.
    Keywords:   SIRT6 ; ageing; development; ecdysone; healthspan; lifespan; metabolism; mitochondria; oxidative stress; physical activity
    DOI:  https://doi.org/10.1111/acel.13576
  45. Free Neuropathol. 2020 ;pii: 33. [Epub ahead of print]1
    Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits.
    Wouter Peelaerts, Liza Bergkvist, Sonia George, Michaela Johnson, Lindsay Meyerdirk, Emily Schulz, Jennifer A Steiner, Zachary Madaj, Jiyan Ma, Katelyn Becker, K Peter R Nilsson, Jerry R Colca, Patrik Brundin.
      Epidemiological studies suggest a link between type-2 diabetes and Parkinson's disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of α-synuclein (αSyn), we hypothesized that inhibiting the MPC might directly inhibit αSyn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of αSyn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based αSyn overexpressing model and a pre-formed fibril (PFF) αSyn seeding model with MSDC-0160. These two models present distinct types of αSyn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models.
    Keywords:  Metabolism; Neurodegeneration; Parkinson’s disease; Synuclein; Synucleinopathy
    DOI:  https://doi.org/10.17879/freeneuropathology-2020-3049
  46. Mol Syndromol. 2022 Feb;13(1): 64-68
    A Patient with Recurrent Severe Hypoglycemic Attacks and Mitochondrial Complex III Deficiency, Nuclear Type 3: a Novel UQCRB Variant.
    Merve Koç Yekedüz, Ümmühan Öncül, Engin Köse, Fatih Ezgü, Fatma Tuba Eminoğlu.
      Common causes of hypoglycemia include hyperinsulinism, hormonal deficiencies, fatty acid oxidation disorders, and glycogen storage diseases; however, rare causes should also be considered for the condition. Mitochondrial complex III deficiency shows an autosomal recessive or a mitochondrial inheritance pattern. To date, mitochondrial complex III deficiency, nuclear type 3 attributable to a pathogenic variant of the UQCRB gene (MIM 615158) has been identified in only 2 pediatric patients; both presented with hypoglycemia and lactic acidosis. In this paper, we present a patient with mitochondrial complex III deficiency, nuclear type 3, UQCRB variant associated with acute hypoglycemia and lactic acidosis episodes. The male patient was admitted on the first day of life with tachypnea, metabolic acidosis, and hypoglycemia. Up to 10 years of age, he was admitted 7 times with abdominal pain, vomiting, and fever. His blood tests revealed hypoglycemia, metabolic acidosis, and hyperlactatemia. At 10 years of age, a whole-exome sequencing (WES) analysis was performed identifying a homozygous c.309_313delAGAAA (p.Glu104ArgfsTer10) pathogenic variant of the UQCRB gene. Once the common causes of hypoglycemia are excluded, it is essential to perform a WES analysis for other rare causes. Thus, rare disorders such as mitochondrial complex III deficiency can be diagnosed.
    Keywords:  Hypoglycemia; Lactic acidosis; Mitochondrial complex III deficiency; UQCRB pathogenic variant
    DOI:  https://doi.org/10.1159/000517761
  47. Neurosci Lett. 2022 Mar 01. pii: S0304-3940(22)00119-7. [Epub ahead of print] 136562
    Transcutaneous auricular vagal nerve stimulation inhibits limbic-regional P2X7R expression and reverses depressive-like behaviors in Zucker diabetic fatty rats.
    Yutian Yu, Xun He, Yu Wang, Jinling Zhang, Chunzhi Tang, Peijing Rong.
      Zucker diabetic fatty (ZDF) rats develop type 2 diabetes (T2D) along with depressive-like behaviors. Transcutaneous auricular vagal nerve stimulation (taVNS) has antidiabetic and antidepressant-like effects in ZDF rats; however, the underlying antidepressant-like mechanisms are unclear. The purinergic receptor P2X7R, which is related to inflammation and depression, is upregulated in the limbic brain regions of depressed patients and rodents and is considered as a potential therapeutic target. Thus, this study aimed to provide preliminary evidence at the molecular level of taVNS antidepressant-like effect in ZDF rats through testing their limbic-regional P2X7R expression. ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Body weight and blood glucose levels were monitored weekly. Depressive-like behaviors were evaluated with the open-field test (OFT) and forced swimming test (FST). Limbic-regional P2X7R expression was examined by western blotting (WB). P2X7R expressing cells were detected by immunohistochemistry (IHC). Compared to their lean littermates (ZL rats), ZDF rats developed obesity, hyperglycemia, and depressive-like behaviors with elevated limbic-regional P2X7R expression. taVNS but not tnVNS lowered body weight, reduced and stabilized blood glucose levels, suppressed limbic-regional P2X7R expression, and reversed the depressive-like behaviors. P2X7R was found primarily expressed in ZDF rats' limbic-regional astrocytes. In conclusion, taVNS inhibits ZDF rats' limbic-regional P2X7R expression, which may be one of the taVNS antidepressant-like mechanisms.
    Keywords:  antidepressant-like; antidiabetic; astrocytes; limbic brain regions; vagal nerve stimulation (VNS)
    DOI:  https://doi.org/10.1016/j.neulet.2022.136562
  48. Sci Rep. 2022 Feb 28. 12(1): 3303
    Brain lipidomics and neurodevelopmental outcomes in intrauterine growth restricted piglets fed dairy or vegetable fat diets.
    Nicole L Henriksen, Karina S Asmussen, Xiaoyu Pan, Ping-Ping Jiang, Yuki Mori, Line I Christiansen, Richard R Sprenger, Christer S Ejsing, Stanislava Pankratova, Thomas Thymann.
      Breast milk has neurodevelopmental advantages compared to infant formula, especially in low-birth-weight infants, which may in part relate to the fat source. This study compared neurodevelopmental outcomes in three-day-old normal birth weight (NBW) and intrauterine growth restricted (IUGR) piglets fed a formula diet with either vegetable oil (VEG) or bovine milk fat sources (MILK) for three weeks in a 2 × 2 factorial design. Behavioural tests, lipidomics, MRI and RNA sequencing analyses of plasma and brain tissue were conducted. The absolute levels of 82% and 11% of lipid molecules were different between dietary groups in plasma and hippocampus, respectively. Of the lipid molecules with differential abundance in the hippocampus, the majority were upregulated in MILK versus VEG, and they mainly belonged to the group of glycerophospholipids. Lower absolute brain weights, absolute grey and white matter volumes and behaviour and motor function scores, and higher relative total brain weights were present in IUGR compared to NBW with minor influence of diet. Cognitive function and cerebellar gene expression profiles were similar for dietary and weight groups, and overall only minor interactive effects between diet and birth weight were observed. Overall, we show that the dietary fat source influences the plasma and to a lesser degree the hippocampal lipidome and is unable to improve on IUGR-induced brain structural and functional impairments.
    DOI:  https://doi.org/10.1038/s41598-022-07133-3
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