bims-medebr 2022-10-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–10–02
ten papers selected by
Regina F. Fernández, Johns Hopkins University

Implications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases.
Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism.
Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion.
Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.
Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.
Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.
Fetal brain development in congenital heart disease.
Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction.
Potential Therapeutic Effects of Short-chain Fatty Acids on Chronic Pain.
Lysophosphatidic acid signaling via LPA6 : a negative modulator of developmental oligodendrocyte maturation.

Neurobiol Dis. 2022 Sep 22. pii: S0969-9961(22)00266-2. [Epub ahead of print]174 105874

Implications of glial metabolic dysregulation in the pathophysiology of neurodegenerative diseases.

Ruqayya Afridi, Md Habibur Rahman, Kyoungho Suk.

  Glial cells are the most abundant cells of the brain, outnumbering neurons. These multifunctional cells are crucial for maintaining brain homeostasis by providing trophic and nutritional support to neurons, sculpting synapses, and providing an immune defense. Glia are highly plastic and undergo both structural and functional alterations in response to changes in the brain microenvironment. Glial phenotypes are intimately regulated by underlying metabolic machinery, which dictates the effector functions of these cells. Altered brain energy metabolism and chronic neuroinflammation are common features of several neurodegenerative diseases. Microglia and astrocytes are the major glial cells fueling the ongoing neuroinflammatory process, exacerbating neurodegeneration. Distinct metabolic perturbations in microglia and astrocytes, including altered carbohydrate, lipid, and amino acid metabolism have been documented in neurodegenerative diseases. These disturbances aggravate the neurodegenerative process by potentiating the inflammatory activation of glial cells. This review covers the recent advances in the molecular aspects of glial metabolic changes in the pathophysiology of neurodegenerative diseases. Finally, we discuss studies exploiting glial metabolism as a potential therapeutic avenue in neurodegenerative diseases.

Keywords:  Astrocyte; Glia; Metabolism; Microglia; Neurodegeneration; Neuroinflammation; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.nbd.2022.105874
Neurochem Res. 2022 Sep 29.

Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism.

Madhu Babu Pasula, Prabhat R Napit, Abdulrahman Alhamyani, Sagor C Roy, Paul W Sylvester, Khaggeswar Bheemanapally, Karen P Briski.

  The plasma membrane glucose transporter-2 (GLUT2) monitors brain cell uptake of the critical nutrient glucose, and functions within astrocytes of as-yet-unknown location to control glucose counter-regulation. Hypothalamic astrocyte-neuron metabolic coupling provides vital cues to the neural glucostatic network. Current research utilized an established hypothalamic primary astrocyte culture model along with gene knockdown tools to investigate whether GLUT2 imposes sex-specific regulation of glucose/energy sensor function and glycogen metabolism in this cell population. Data show that GLUT2 stimulates or inhibits glucokinase (GCK) expression in glucose-supplied versus -deprived male astrocytes, but does not control this protein in female. Astrocyte 5'-AMP-activated protein kinaseα1/2 (AMPK) protein is augmented by GLUT2 in each sex, but phosphoAMPKα1/2 is coincidently up- (male) or down- (female) regulated. GLUT2 effects on glycogen synthase (GS) diverges in the two sexes, but direction of this control is reversed by glucoprivation in each sex. GLUT2 increases (male) or decreases (female) glycogen phosphorylase-brain type (GPbb) protein during glucoprivation, yet simultaneously inhibits (male) or stimulates (female) GP-muscle type (GPmm) expression. Astrocyte glycogen accumulation is restrained by GLUT2 when glucose is present (male) or absent (both sexes). Outcomes disclose sex-dependent GLUT2 control of the astrocyte glycolytic pathway sensor GCK. Data show that glucose status determines GLUT2 regulation of GS (both sexes), GPbb (female), and GPmm (male), and that GLUT2 imposes opposite control of GS, GPbb, and GPmm profiles between sexes during glucoprivation. Ongoing studies aim to investigate molecular mechanisms underlying sex-dimorphic GLUT2 regulation of hypothalamic astrocyte metabolic-sensory and glycogen metabolic proteins, and to characterize effects of sex-specific astrocyte target protein responses to GLUT2 on glucose regulation.

Keywords:  AMPK; GLUT2; Glycogen; Glycogen phosphorylase; Sex differences; glucokinase

DOI:  https://doi.org/10.1007/s11064-022-03757-z
Nat Commun. 2022 Sep 30. 13(1): 5761

Lipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion.

Anastasiya Strembitska, Gwenaël Labouèbe, Alexandre Picard, Xavier P Berney, David Tarussio, Maxime Jan, Bernard Thorens.

The counterregulatory response to hypoglycemia that restores normal blood glucose levels is an essential physiological function. It is initiated, in large part, by incompletely characterized brain hypoglycemia sensing neurons that trigger the secretion of counterregulatory hormones, in particular glucagon, to stimulate hepatic glucose production. In a genetic screen of recombinant inbred BXD mice we previously identified Agpat5 as a candidate regulator of hypoglycemia-induced glucagon secretion. Here, using genetic mouse models, we demonstrate that Agpat5 expressed in agouti-related peptide neurons is required for their activation by hypoglycemia, for hypoglycemia-induced vagal nerve activity, and glucagon secretion. We find that inactivation of Agpat5 leads to increased fatty acid oxidation and ATP production and that suppressing Cpt1a-dependent fatty acid import into mitochondria restores hypoglycemia sensing. Collectively, our data show that AgRP neurons are involved in the control of glucagon secretion and that Agpat5, by partitioning fatty acyl-CoAs away from mitochondrial fatty acid oxidation and ATP generation, ensures that the fall in intracellular ATP, which triggers neuronal firing, faithfully reflects changes in glycemia.

DOI: https://doi.org/10.1038/s41467-022-33484-6
Proc Natl Acad Sci U S A. 2022 Oct 04. 119(40): e2210353119

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.

Menglan He, Alvin C Y Kuk, Mei Ding, Cheen Fei Chin, Dwight L A Galam, Jie Min Nah, Bryan C Tan, Hui Li Yeo, Geok Lin Chua, Peter I Benke, Markus R Wenk, Lena Ho, Federico Torta, David L Silver.

  The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.

Keywords:  Mfsd2a; autophagy; lysosome; phospholipid; transporter

DOI:  https://doi.org/10.1073/pnas.2210353119
eNeuro. 2022 Sep 27. pii: ENEURO.0253-22.2022. [Epub ahead of print]

Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry.

Mohammed H Sarikahya, Samantha Cousineau, Marta De Felice, Kendrick Lee, Karen Wong, Marieka V DeVuono, Tony Jung, Mar Rodríguez-Ruiz, Tsun Hay Jason Ng, Dana Gummerson, Emma Proud, Daniel B Hardy, Ken K-C Yeung, Walter Rushlow, Steven R Laviolette.

  Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3mg/kg) from gestational day (GD) 7 until GD22. Anxiety-like, depressive-like, and reward-seeking behaviour, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was performed at prepubescence and adulthood. We report PCE induces behavioral, neuronal, and molecular alterations in the mesolimbic system in male and female offspring, resembling neuropsychiatric endophenotypes. Additionally, PCE resulted in profound dysregulation of critical fatty acid pathways in the developing brain lipidome. Female progeny exhibited greater alterations to fatty acid levels at prepubescence but recovered from these deficits by early adulthood. In contrast, males exhibited persistent fatty acid deficits into adulthood. Moreover, both sexes maintained enduring abnormalities in glutamatergic/GABAergic function in the nucleus accumbens. These findings identify several novel long-term risks of maternal cannabis use and demonstrate for the first time, sex-related effects of maternal cannabinoid exposure directly in the developing neural lipidome.Significance StatementPrenatal cannabinoid exposure (PCE) is growing in prevalence and the long-term effects on fetal brain development are largely unknown. Our study provides novel evidence that chronic prenatal THC exposure can induce long-lasting alterations in mesolimbic function that differentially impacts the male vs. female brains. We also demonstrate for the first time that PCE can induce profound lipidomic adaptations that may account for these neuropathophysiological sequelae.

Keywords:  MALDI IMS; electrophysiology; lipidomics; mesolimbic system; prenatal cannabis exposure; sex differences

DOI:  https://doi.org/10.1523/ENEURO.0253-22.2022
Nutr Res. 2022 Aug 12. pii: S0271-5317(22)00073-2. [Epub ahead of print]106 72-84

Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.

Sarika Yadav, Ashish Dwivedi, Anurag Tripathi, Amit Kumar Tripathi.

  Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut-brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed.

Keywords:  Histone deacetylase; Mitochondrial nutrients; Neurodegenerative disease; Short-chain fatty acids

DOI:  https://doi.org/10.1016/j.nutres.2022.07.007
Can J Cardiol. 2022 Sep 26. pii: S0828-282X(22)00893-5. [Epub ahead of print]

Fetal brain development in congenital heart disease.

Shabnam Peyvandi, Caitlin Rollins.

Neurodevelopmental impairments are the most common extracardiac morbidities among patients with complex congenital heart disease (CHD) across the lifespan. Robust clinical research in this area has revealed several cardiac, medical and social factors that can contribute to neurodevelopmental outcome in the context of CHD. Studies utilizing brain MRI have been instrumental in identifying quantitative and qualitative difference in brain structure and maturation in this patient population. Full-term newborns with complex CHD are known to have abnormal microstructural and metabolic brain development with patterns similar to those seen in premature infants at approximately 34-36 weeks gestation. With the advent of fetal brain MRI, it is now known that these brain abnormalities begin in utero, as early as the 3rd trimester. Importantly, disturbed brain development in utero is now known to be independently associated with neurodevelopmental outcome in early childhood, making the prenatal period an important timeframe for potential interventions. Advances in fetal brain MRI provide a robust imaging tool to utilize in future neuroprotective clinical trials. The causes of abnormal fetal brain development are multi-factorial and include cardiovascular physiology, genetic abnormalities, placental impairment, and other environmental and social factors. This review provides an overview of current knowledge of brain development in the context of CHD, common prenatal imaging tools to evaluate the developing fetal brain in CHD and known risk factors contributing to brain immaturity.

DOI: https://doi.org/10.1016/j.cjca.2022.09.020
Food Funct. 2022 Sep 30.

Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction.

Dan Chen, Ying-Ying Wang, Sheng-Peng Li, Hui-Min Zhao, Feng-Juan Jiang, Ya-Xian Wu, Ying Tong, Qing-Feng Pang.

Intrauterine growth restriction (IUGR), one of the major complications of pregnancy, is characterized by low birth weight and results in higher risks for long-term problems including developing metabolic and cardiovascular diseases. Short-chain fatty acids (SCFAs), especially propionate, have been reported to correct glucose and lipid disorders in metabolic diseases. We hypothesized that maternal propionate supplementation could prevent glucose and lipid metabolic disturbance in hypoxia-induced IUGR. Here, in our study, maternal hypoxia was induced from gestational day (GD) 11 to GD 17.5 to establish an IUGR mouse model. Maternal propionate treatment reversed reduced birth weight in male IUGR offspring. Hepatic transcriptomics demonstrated that SP treatment significantly lowered glucose and lipid metabolism-related genes (Scd1, G6pc, Pck1 and Fasl) in IUGR offspring. KOG enrichment analysis showed that propionate-induced down-regulated differential expressed genes (DEGs) mainly belonged to lipid transport and metabolism. KEGG enrichment results showed that the down-regulated DEGs were mostly enriched in PPAR and FoxO signaling pathways. We also found that maternal oral administration of SP decreased serum lipid content, attenuated hepatic insulin resistance and liver lipid accumulation, reduced hepatic key gene expressions of gluconeogenesis and lipogenesis, increased energy expenditure and improved liver function in 11-week-old male IUGR offspring. These results indicate that maternal propionate supplementation increases birth weight and corrects hepatic glucose and lipid metabolic disturbance and energy expenditure in male mice born with IUGR, which may provide a basis for using propionate to treat IUGR disease.

DOI: https://doi.org/10.1039/d2fo01481e
Curr Neuropharmacol. 2022 Sep 27.

Potential Therapeutic Effects of Short-chain Fatty Acids on Chronic Pain.

Yuanyuan Tang, Juan Du, Hongfeng Wu, Mengyao Wang, Sufang Liu, Feng Tao.

  The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.

Keywords:  chronic pain; gut microbiome; gut- brain communication; metabolites; short-chain fatty acids

DOI:  https://doi.org/10.2174/1570159X20666220927092016
J Neurochem. 2022 Sep 25.

Lysophosphatidic acid signaling via LPA6 : a negative modulator of developmental oligodendrocyte maturation.

Samantha A Spencer, Edna Suárez-Pozos, Jazmín Soto Verdugo, Huiqun Wang, Fatemah S Afshari, Li Guo, Susmita Manam, Daisuke Yasuda, Arturo Ortega, James A Lister, Satoshi Ishii, Yan Zhang, Babette Fuss.

  The developmental process of central nervous system (CNS) myelin sheath formation is characterized by well-coordinated cellular activities ultimately ensuring rapid and synchronized neural communication. During this process, myelinating CNS cells, namely oligodendrocytes (OLGs), undergo distinct steps of differentiation, whereby the progression of earlier maturation stages of OLGs represents a critical step toward the timely establishment of myelinated axonal circuits. Given the complexity of functional integration, it is not surprising that OLG maturation is controlled by a yet fully to be defined set of both negative and positive modulators. In this context, we provide here first evidence for a role of lysophosphatidic acid (LPA) signaling via the G protein-coupled receptor LPA6 as a negative modulatory regulator of myelination-associated gene expression in OLGs. More specifically, cell surface accessibility of LPA6 was found to be restricted to the earlier maturation stages of differentiating OLGs, and OLG maturation was found to occur precociously in Lpar6 knockout mice. To further substantiate these findings, a novel small molecule ligand with selectivity for preferentially LPA6 and LPA6 agonist characteristics was functionally characterized in vitro in primary cultures of rat OLGs and in vivo in the developing zebrafish. Utilizing this approach, a negative modulatory role of LPA6 signaling in OLG maturation could be corroborated. During development, such a functional role of LPA6 signaling likely serves to ensure timely coordination of circuit formation and myelination. Under pathological conditions as seen in the major human demyelinating disease multiple sclerosis (MS), however, persistent LPA6 expression and signaling in OLGs can be seen as an inhibitor of myelin repair. Thus, it is of interest that LPA6 protein levels appear elevated in MS brain samples, thereby suggesting that LPA6 signaling may represent a potential new druggable pathway suitable to promote myelin repair in MS.

Keywords:  computational ligand-protein docking; lipid signaling; multiple sclerosis; myelination; oligodendrocyte; small molecule ligands

DOI:  https://doi.org/10.1111/jnc.15696