bims-medebr 2023-09-24 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–09–24
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.
Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.
Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice.
Astrocyte metabolism and signaling pathways in the CNS.
Altered markers of mitochondrial function in adults with autism spectrum disorder.
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.
A hydrolyzed lipid blend diet promotes myelination in neonatal piglets in a region and concentration-dependent manner.
Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease.
Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).
Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.
Case report: Diagnosis of a patient with Sifrim-Hitz-Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency.
GLUT-1 transporter deficiency presenting as hemiplegic migraine in an adult.
Brain-body communication in metabolic control.
Neuronal AR regulates glucose homeostasis and energy expenditure in lean female mice with androgen excess.
Human sphingomyelin synthase 1 generates diacylglycerol in the presence and absence of ceramide via multiple enzymatic activities.

J Epilepsy Res. 2023 Jun 30. 13(1): 1-6

Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

Saman Hazany, Brittany DeClouette, Jessica Lowe, Darryl H Hwang, Paul E Kim, Stefan Bluml, Arthur Partikian.

   Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD.
Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months.
Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes.
Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.

Keywords:  1H MRS; Epilepsy; GSH; Glutathione; Ketogenic diet; MR spectroscopy

DOI:  https://doi.org/10.14581/jer.23001
Neuropharmacology. 2023 Sep 18. pii: S0028-3908(23)00306-4. [Epub ahead of print]240 109716

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway.

Zhao-Jun Wang, Xin-Ru Li, Shi-Fan Chai, Wei-Ran Li, Shuo Li, Meng Hou, Jia-Lei Li, Yu-Cai Ye, Hong-Yan Cai, Christian Hölscher, Mei-Na Wu.

  Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer's disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampus of 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD. The mice were injected with semaglutide on alternate days for 30 days, followed by behavioral experiments including open field test, new object recognition test, and Y-maze. The content of glucose in the brain was also measured by using 18FDG-PET-CT scans. We measured the expression of Aβ and tau in the hippocampus, observed the expression of GLUT4 which is downstream of SIRT1, and tested the Glucose oxidase assay (GOD-POD) and Hexokinase (HK) in HT22 cells. Here, we found in the 3xTg mouse model of AD and in cultured HT22 mouse neurons that SIRT1 signaling is involved in the impairment of glucose metabolism in AD. Semaglutide can increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xTg mice, accompanied by an improvement in learning and memory, decreased in Aβ plaques and neurofibrillary tangles. In addition, we further demonstrated that semaglutide improved glucose metabolism in the brain of 3xTg mice in vitro, semaglutide promoted glycolysis and improved glycolytic disorders, and increased the membrane translocation of GLUT4 in cultured HT22 cells. These effects were blocked by the SIRT1 inhibitor (EX527). These findings indicate that semaglutide can regulate the expression of GLUT4 to mediate glucose transport through SIRT1, thereby improving glucose metabolism dysfunction in AD mice and cells. The present study suggests that SIRT1/GLUT4 signaling pathway may be an important mechanism for GLP-1R to promote glucose metabolism in the brain, providing a reliable strategy for effective therapy of AD.

Keywords:  Alzheimer's disease; GLUT4; Glucagon-like peptide-1 receptor; Glucose metabolism dysfunction; SIRT1

DOI:  https://doi.org/10.1016/j.neuropharm.2023.109716
Nat Commun. 2023 09 16. 14(1): 5749

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice.

Katia Monsorno, Kyllian Ginggen, Andranik Ivanov, An Buckinx, Arnaud L Lalive, Anna Tchenio, Sam Benson, Marc Vendrell, Angelo D'Alessandro, Dieter Beule, Luc Pellerin, Manuel Mameli, Rosa Chiara Paolicelli.

Microglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced AMPA/GABA ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in mouse brain development and adult behavior.

DOI: https://doi.org/10.1038/s41467-023-41502-4
Front Neurosci. 2023 ;17 1217451

Astrocyte metabolism and signaling pathways in the CNS.

Yong-Mei Zhang, Ying-Bei Qi, Ya-Nan Gao, Wen-Gang Chen, Ting Zhou, Yi Zang, Jia Li.

  Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.

Keywords:  astrocyte; energy imbalance; metabolism; neural circuit; neurological disorders

DOI:  https://doi.org/10.3389/fnins.2023.1217451
Autism Res. 2023 Sep 16.

Altered markers of mitochondrial function in adults with autism spectrum disorder.

Kathrin Nickel, Mia Menke, Dominique Endres, Kimon Runge, Sara Tucci, Anke Schumann, Katharina Domschke, Ludger Tebartz van Elst, Simon Maier.

  Previous research suggests potential mitochondrial dysfunction and changes in fatty acid metabolism in a subgroup of individuals with autism spectrum disorder (ASD), indicated by higher lactate, pyruvate levels, and mitochondrial disorder prevalence. This study aimed to further investigate potential mitochondrial dysfunction in ASD by assessing blood metabolite levels linked to mitochondrial metabolism. Blood levels of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, pyruvate, free and total carnitine, as well as acylcarnitines were obtained in 73 adults with ASD (47 males, 26 females) and compared with those of 71 neurotypical controls (NTC) (44 males, 27 females). Correlations between blood parameters and psychometric ASD symptom scores were also explored. Lower CK (pcorr = 0.045) levels were found exclusively in males with ASD compared to NTC, with no such variation in females. ALT and AST levels did not differ significantly between both groups. After correction for antipsychotic and antidepressant medication, CK remained significant. ASD participants had lower serum lactate levels (pcorr = 0.036) compared to NTC, but pyruvate and carnitine concentrations showed no significant difference. ASD subjects had significantly increased levels of certain acylcarnitines, with a decrease in tetradecadienoyl-carnitine (C14:2), and certain acylcarnitines correlated significantly with autistic symptom scores. We found reduced serum lactate levels in ASD, in contrast to previous studies suggesting elevated lactate or pyruvate. This difference may reflect the focus of our study on high-functioning adults with ASD, who are likely to have fewer secondary genetic conditions associated with mitochondrial dysfunction. Our findings of significantly altered acylcarnitine levels in ASD support the hypothesis of altered fatty acid metabolism in a subset of ASD patients.

Keywords:  acylcarnitines; autism spectrum disorder; carnitine; creatine kinase; lactate; mitochondria; pyruvate

DOI:  https://doi.org/10.1002/aur.3029
PLoS Genet. 2023 Sep;19(9): e1010893

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Dongwei Xu, Alec Vincent, Andrés González-Gutiérrez, Benjamin Aleyakpo, Sharifah Anoar, Ashling Giblin, Magda L Atilano, Mirjam Adams, Dunxin Shen, Annora Thoeng, Elli Tsintzas, Marie Maeland, Adrian M Isaacs, Jimena Sierralta, Teresa Niccoli.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

DOI: https://doi.org/10.1371/journal.pgen.1010893
J Neurosci Res. 2023 Sep 22.

A hydrolyzed lipid blend diet promotes myelination in neonatal piglets in a region and concentration-dependent manner.

Allison Y Louie, Laurie A Rund, Karin A Komiyama-Kasai, Kelsie E Weisenberger, Kayla L Stanke, Ryan J Larsen, Brian J Leyshon, Matthew J Kuchan, Tapas Das, Andrew J Steelman.

  The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. Here, we assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. At postnatal day 28/29, magnetic resonance imaging (MRI) was performed to assess changes to brain development, followed by brain collection for microscopic analyses of myelin in targeted regions using CLARITY tissue clearing, immunohistochemistry, and electron microscopy techniques. Sow-reared piglets exhibited the highest overall brain white matter volume by MRI. However, a 25% HF diet resulted in the greatest total myelin density in the prefrontal cortex based on 3D modeling analysis of myelinated filaments. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the PFC and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. These findings indicate that HF promoted myelination in the neonatal piglet in a region- and concentration-dependent manner.

Keywords:  g-ratio; hydrolyzed fat; myelin; node length; postnatal; white matter

DOI:  https://doi.org/10.1002/jnr.25243
J Alzheimers Dis. 2023 Sep 14.

Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease.

Jan Krzysztof Blusztajn, Nurgul Aytan, Thekkelnaycke Rajendiran, Tiffany J Mellott, Tanu Soni, Charles F Burant, Geidy E Serrano, Thomas G Beach, Honghuang Lin, Thor D Stein.

   BACKGROUND: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression.
OBJECTIVE: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits.
METHODS: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288).
RESULTS: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter.
CONCLUSIONS: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.

Keywords:  Alzheimer’s disease; cerebral cortex; cerebrosides; gray matter; lipidomics; monogalactosyldiacylglycerol; white matter

DOI:  https://doi.org/10.3233/JAD-230543
J Alzheimers Dis. 2023 Sep 11.

Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).

Suzanne M de la Monte.

  Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.

Keywords:  Aging; Alzheimer’s disease; brain; mTOR; neurodegeneration; neuroinflammation; type 3 diabetes; vascular disease; white matter

DOI:  https://doi.org/10.3233/JAD-230555
iScience. 2023 Oct 20. 26(10): 107780

Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.

Margaret E Maes, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E Pohl, Sandra Siegert.

  Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.

Keywords:  Biological sciences; Natural sciences; Neuroscience; Physiology; Sensory neuroscience; Systems neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.107780
Yonsei Med J. 2023 Oct;64(10): 625-632

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.

Young-Suk Choi, Jae Eun Song, Eosu Kim, Chul Hoon Kim, Jong Eun Lee, Ho-Taek Song.

   PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer's disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1-13C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism.
MATERIALS AND METHODS: ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1-13C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells.
RESULTS: As a perfusion marker, the total 13C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (Kpl) from [1-13C]pyruvate to [1-13C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ratio and lactate generation.
CONCLUSION: Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with enhanced cognitive performance and increased conversion of HP [1-13C]pyruvate to HP [1-13C]lactate.

Keywords:  Alzheimer's disease; agmatine; hyperpolarized 13C; lactate; magnetic resonance spectroscopy

DOI:  https://doi.org/10.3349/ymj.2022.0554
Front Pediatr. 2023 ;11 1230056

Case report: Diagnosis of a patient with Sifrim-Hitz-Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency.

Naim Zeka, Eris Zeka, Esra Zhubi, Ilir Hoxha.

   Background: It is generally recognized that genetic metabolic disorders can result in neurological symptoms such as seizures, developmental delay, and intellectual disability. Heterogeneous clinical presentations make the diagnosis challenging.
Case presentation: In this case report, we present a unique and complex genetic disorder observed in a female patient who exhibited three pathogenic gene variants in the KCNT1, ACADM, and CHD4 genes. The convergence of these variants resulted in a multifaceted clinical presentation characterized by severe seizures of combined focal and generalized onset, metabolic dysfunction, and neurodevelopmental abnormalities. The identification and functional characterization of these gene variants shed light on the intricate interplay between these genes and the patient's phenotype. EEG revealed an epileptiform abnormality which presented in the inter-ictal period from the left frontal-central area and in the ictal period from the left mid-temporal area. The brain MRI revealed volume loss in the posterior periventricular area and parietal parenchyma, myelin destruction with no sign of hypoxic involvement, and left dominant enlargement of the lateral ventricles secondary to loss of central parenchyma. The patient was diagnosed through exome sequencing with Sifrim-Hitz-Weiss syndrome, development and epileptic encephalopathy-14, and medium-chain acyl-CoA dehydrogenase deficiency. An antiseizure medication regimen with valproic acid, levetiracetam, phenobarbital, and clonazepam was initiated. However, this led to only partial control of the seizures.
Conclusion: Clinical follow-up of the patient will further define the clinical spectrum of KCNT1, ACADM, and CHD4 gene variants. It will also determine the long-term efficacy of the treatment of seizures and the development of precision medicine for epilepsy syndromes due to gain-of-function variants. Special emphasis should be put on the role and importance of large-scale genomic testing in understanding and diagnosing complex phenotypes and atypical epileptic syndromes.

Keywords:  Sifrim–Hitz–Weiss syndrome; developmental and epileptic encephalopathy; genetic variants; medium-chain acyl-CoA dehydrogenase deficiency; neurodevelopmental delay; seizure

DOI:  https://doi.org/10.3389/fped.2023.1230056
Acta Neurol Belg. 2023 Sep 21.

GLUT-1 transporter deficiency presenting as hemiplegic migraine in an adult.

Simon Horckmans, Wim Van Paesschen.



Keywords:  GLUT1 transporter deficiency; Hemiplegic migraine; SLC2A1

DOI:  https://doi.org/10.1007/s13760-023-02387-8
Trends Endocrinol Metab. 2023 Sep 14. pii: S1043-2760(23)00167-4. [Epub ahead of print]

Brain-body communication in metabolic control.

Alessandro Furlan, Paul Petrus.

  A thorough understanding of the mechanisms controlling energy homeostasis is needed to prevent and treat metabolic morbidities. While the contribution of organs such as the liver, muscle, adipose tissue, and pancreas to the regulation of energy has received wide attention, less is known about the interplay with the nervous system. Here, we highlight the role of the nervous systems in regulating metabolism beyond the classic hypothalamic endocrine signaling models and discuss the contribution of circadian rhythms, higher brain regions, and sociodemographic variables in the energy equation. We infer that interdisciplinary approaches are key to conceptually advancing the current research frontier and devising innovative therapies to prevent and treat metabolic disease.

Keywords:  circadian rhythms; interorgan communication; metabolic disease; metabolism; nervous system

DOI:  https://doi.org/10.1016/j.tem.2023.08.014
Endocrinology. 2023 Sep 21. pii: bqad141. [Epub ahead of print]

Neuronal AR regulates glucose homeostasis and energy expenditure in lean female mice with androgen excess.

Vaibhave Ubba, Serene Joseph, Olubusayo Awe, Dustin Jones, Milan K Dsilva, Mingxiao Feng, Junjiang Wang, Xiaomin Fu, Razeen J Akbar, Brittany H Bodnar, Wenhui Hu, Hong Wang, Xiaofeng Yang, Ling Yang, Peixin Yang, Rexford Ahima, Sara Divall, Sheng Wu.

  Hyperandrogenemia and polycystic ovarian syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system (CNS) mediates metabolism under normal and increased androgen conditions in female mice. The neuron specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. Glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-DHT mice compared to Con-DHT mice after 4-months of DHT treatment. Heat production and food intake was higher in Con-DHT mice compared to Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal AR. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice compared to the Con-veh mice, and this effect was attenuated in the SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared to Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

Keywords:  DHT; PCOS; androgen receptor; energy expenditure; glucose; neuron

DOI:  https://doi.org/10.1210/endocr/bqad141
FEBS Lett. 2023 Sep 16.

Human sphingomyelin synthase 1 generates diacylglycerol in the presence and absence of ceramide via multiple enzymatic activities.

Rika Suzuki, Chiaki Murakami, Kamila Dilimulati, Kyoko Atsuta-Tsunoda, Takuma Kawai, Fumio Sakane.

  Sphingomyelin (SM) synthase 1 (SMS1), which is involved in lipodystrophy, deafness, and thrombasthenia, generates diacylglycerol (DG) and SM using phosphatidylcholine (PC) and ceramide as substrates. Here, we found that SMS1 possesses DG-generating activities via hydrolysis of PC and phosphatidylethanolamine (PE) in the absence of ceramide and ceramide phosphoethanolamine synthase (CPES) activity. In the presence of the same concentration (4.7 mol%) of PC and ceramide, the amounts of DG produced by SMS and PC-phospholipase C (PLC) activities of SMS1 were approximately 65% and 35% of total DG production, respectively. PC-PLC activity showed substrate selectivity for saturated and/or monounsaturated fatty acid-containing PC species. A PC-PLC/SMS inhibitor, D609, inhibited only SMS activity. Mn2+ inhibited only PC-PLC activity. Intriguingly, DG attenuated SMS/CPES activities. Our study indicates that SMS1 is a unique enzyme with PC-PLC/PE-PLC/SMS/CPES activities.

Keywords:  Ceramide; Ceramide phosphoethanolamine synthase; D609; Diacylglycerol; Phosphatidylcholine-phospholipase C; Sphingomyelin synthase

DOI:  https://doi.org/10.1002/1873-3468.14735