bims-medebr 2021-11-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2021‒11‒21
six papers selected by
Regina F. Fernández
Johns Hopkins University

The Majority of Brain Palmitic Acid is Maintained by Lipogenesis from Dietary Sugars and is Augmented in Mice fed Low Palmitic Acid Levels from Birth.
Running the Female Power Grid Across Lifespan Through Brain Estrogen Signaling.
The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury.
Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance.
Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of the Orbitofrontal Cortex Metabolic Networks.
Docosahexaenoic acid reduces hypoglycemia-induced neuronal necroptosis via the peroxisome proliferator-activated receptor γ/nuclear factor-κB pathway.

J Neurochem. 2021 Nov 15.

The Majority of Brain Palmitic Acid is Maintained by Lipogenesis from Dietary Sugars and is Augmented in Mice fed Low Palmitic Acid Levels from Birth.

Mackenzie E Smith, Giulia Cisbani, Adam H Metherel, Richard P Bazinet.

  Previously, results from studies investigating if brain palmitic acid (16:0; PAM) was maintained by either dietary uptake or lipogenesis de novo (DNL) varied. Here, we utilize naturally occurring carbon isotope ratios (13 C/12 C; δ13 C) to uncover the origin of brain PAM. Additionally, we explored brain and liver fatty acid concentration, total brain metabolomic profile, and behaviour. BALB/c dams were equilibrated onto either a low PAM diet (LP; <2%) or high PAM diet (HP; >95%) prior to producing one generation of offspring. Offspring stayed on the respective diet of the dam until 15-weeks of age, at which time the Open Field test was conducted in the offspring, prior to euthanasia and tissue lipid extraction. Although liver PAM was lower in offspring fed the LP diet, as well as female offspring, brain PAM was not affected by diet or sex. Across offspring of either sex on both diets, brain 13 C-PAM revealed compared to dietary uptake, DNL from dietary sugars contributed 68.8%-79.5% and 46.6%-58.0% to the total brain PAM pool by both peripheral and local brain DNL, and local brain DNL alone, respectively. DNL was augmented in offspring fed the LP diet, and the ability to upregulate DNL in the liver or the brain depended on sex. Anxiety-like behaviours were decreased in offspring fed the LP diet and were correlated with markers of LP diet consumption including increased liver 13 C-PAM, warranting further investigation. Altogether, our results indicate that DNL from dietary sugars is a compensatory mechanism to maintain brain PAM in response to a LP diet.

Keywords:  Lipogenesis; Palmitic acid; brain; carbon isotope ratios; compound specific isotope analysis; dietary sugars

DOI:  https://doi.org/10.1111/jnc.15539
Annu Rev Physiol. 2021 Nov 15.

Running the Female Power Grid Across Lifespan Through Brain Estrogen Signaling.

Holly A Ingraham, Candice B Herber, William C Krause.

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required to establish crucial sex differences in energy allocation. However, the immense cellular complexity of these hormone-sensitive brain regions makes it clear that more research is needed to fully appreciate how estrogen modulates neural circuits to regulate physiological and behavioral end points. Such insight is essential for understanding how natural or drug-induced hormone fluctuations across lifespan affect women's health. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-061121-035914
Front Neurol. 2021 ;12 723148

The Therapeutic Potential and Limitations of Ketones in Traumatic Brain Injury.

Savannah Anne Daines.

  Traumatic brain injury (TBI) represents a significant health crisis. To date, no FDA approved pharmacotherapies are available to prevent the neurological deficits caused by TBI. As an alternative to pharmacotherapy treatment of TBI, ketones could be used as a metabolically based therapeutic strategy. Ketones can help combat post-traumatic cerebral energy deficits while also reducing inflammation, oxidative stress, and neurodegeneration. Experimental models of TBI suggest that administering ketones to TBI patients may provide significant benefits to improve recovery. However, studies evaluating the effectiveness of ketones in human TBI are limited. Unanswered questions remain about age- and sex-dependent factors, the optimal timing and duration of ketone supplementation, and the optimal levels of circulating and cerebral ketones. Further research and improvements in metabolic monitoring technology are also needed to determine if ketone supplementation can improve TBI recovery outcomes in humans.

Keywords:  cerebral metabolism; glucose; ketogenic; ketone; ketosis; traumatic brain injury

DOI:  https://doi.org/10.3389/fneur.2021.723148
Proc Natl Acad Sci U S A. 2021 Nov 23. pii: e2112466118. [Epub ahead of print]118(47):

Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance.

Hélène Roumes, Charlotte Jollé, Jordy Blanc, Imad Benkhaled, Carolina Piletti Chatain, Philippe Massot, Gérard Raffard, Véronique Bouchaud, Marc Biran, Catherine Pythoud, Nicole Déglon, Eduardo R Zimmer, Luc Pellerin, Anne-Karine Bouzier-Sore.

  Lactate is an efficient neuronal energy source, even in presence of glucose. However, the importance of lactate shuttling between astrocytes and neurons for brain activation and function remains to be established. For this purpose, metabolic and hemodynamic responses to sensory stimulation have been measured by functional magnetic resonance spectroscopy and blood oxygen level-dependent (BOLD) fMRI after down-regulation of either neuronal MCT2 or astroglial MCT4 in the rat barrel cortex. Results show that the lactate rise in the barrel cortex upon whisker stimulation is abolished when either transporter is down-regulated. Under the same paradigm, the BOLD response is prevented in all MCT2 down-regulated rats, while about half of the MCT4 down-regulated rats exhibited a loss of the BOLD response. Interestingly, MCT4 down-regulated animals showing no BOLD response were rescued by peripheral lactate infusion, while this treatment had no effect on MCT2 down-regulated rats. When animals were tested in a novel object recognition task, MCT2 down-regulated animals were impaired in the textured but not in the visual version of the task. For MCT4 down-regulated animals, while all animal succeeded in the visual task, half of them exhibited a deficit in the textured task, a similar segregation into two groups as observed for BOLD experiments. Our data demonstrate that lactate shuttling between astrocytes and neurons is essential to give rise to both neurometabolic and neurovascular couplings, which form the basis for the detection of brain activation by functional brain imaging techniques. Moreover, our results establish that this metabolic cooperation is required to sustain behavioral performance based on cortical activation.

Keywords:  MRS; brain metabolism; fMRI; learning and memory; monocarboxylate transporter

DOI:  https://doi.org/10.1073/pnas.2112466118
Neurotox Res. 2021 Nov 19.

Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of the Orbitofrontal Cortex Metabolic Networks.

Felipe Schmitz, Josiane S Silveira, Gianina T Venturin, Samuel Greggio, Guilherme Schu, Eduardo R Zimmer, Jaderson Costa Da Costa, Angela T S Wyse.

  Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light-dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.

Keywords:  Anxiety-like behavior; Attention-deficit/hyperactivity disorder; Brain activity; Molecular imaging; Orbitofrontal cortex; Psychostimulant

DOI:  https://doi.org/10.1007/s12640-021-00444-9
Brain Res. 2021 Nov 14. pii: S0006-8993(21)00565-5. [Epub ahead of print]1774 147708

Docosahexaenoic acid reduces hypoglycemia-induced neuronal necroptosis via the peroxisome proliferator-activated receptor γ/nuclear factor-κB pathway.

Lin Huang, Yue Zhou, Zhi-Xian Gou, Feng Zhang, Li-Qun Lu.

  DHA has been shown to be neuroprotective and important to neurogenesis, but its role in HG-induced brain injury and the underlying mechanisms remain unknown. To elucidate the therapeutic effect of DHA, we established a mouse model with insulin-induced hypoglycemic brain injury and an in vitro model of HT-22 cells using a sugar-free medium. DHA treatment significantly reduced neuronal death and improved HG-induced learning and memory deficits. Moreover, DHA inhibited neuronal necroptosis and decreased the concentrations of TNF-α, IL-1β and TNFR1. DHA also activated PPAR-γ and suppressed the NF-κB pathway in mouse brain tissues. In vitro, DHA treatment restored the viability and decreased necroptosis of HT-22 cells treated with glucose deprivation. However, the inhibition of PPAR-γ with T0070907 reversed neuroprotective and anti-necroptosis effects of DHA in HG-induced brain injury, which is associated with the activation of the downstream NF-κB pathway. We conclude that DHA displays a protective effect against HG-induced brain injury through the PPAR-γ/NF-κB pathway and represents a promising method to prevent HG-induced brain injury.

Keywords:  Docosahexaenoic acid; Hypoglycemia; Necroptosis; Neuron death; PPAR-γ,neonate

DOI:  https://doi.org/10.1016/j.brainres.2021.147708