Fats for thoughts: An update on brain fatty acid metabolism

Romano, Adele; Koczwara, Justyna Barbara; Gallelli, Cristina Anna; Vergara, Daniele; Bonaventura, Maria Vittoria Micioni Di; Gaetani, Silvana; Giudetti, Anna Maria

doi:10.1016/j.biocel.2016.12.015

Cited by 88 publications

(79 citation statements)

References 47 publications

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“…While the traditional view posits that the brain, encompassing neurons, glia cells, and blood vessels utilizes glucose exclusively as an energy source, findings from astroglia challenge this view. Recent research shows that up to 20% of the energy production in the brain arises from fatty acids (Romano et al, 2017;Snowden et al, 2017). Thus, the brain uses an energy-efficient process where the complete oxidation of a 16-carbon palmitic acid yields 112 molecules of ATP.…”

Section: Discussionmentioning

confidence: 99%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies. SynopsisEnergy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin. ACKNOWLEDGMENTSWe thank Nancy Busija, MA, for editing the manuscript. We thank Dana Liu for technical help.

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Section: Discussionmentioning

confidence: 99%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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“…For example, the in vivo reduction in increased PPAR levels in astrocytes reduces mitochondrial dysfunction, decreases inflammation, and increases cellular antioxidant defences [139][140][141]. These data are also of importance from the perspective of improving astrocyte function as all these factors are also involved in driving and maintaining a reactive state in these glial cells [142].…”

Section: Consequences Of Ketogenesis and Ketolysis In The Cnsmentioning

confidence: 98%

“…Other triggers include glucose deprivation, increased levels of ATP and other gliotransmitters, and activation of surface tolllike receptors by commensal lipopolysaccharide (LPS) originally translocated from the intestine. It is important to note that the development of reactive astrogliosis provoked by these stimuli, particularly the inflammatory mediators such as the PICs, ROS, and NO, is accomplished via major changes in astrocyte gene transcription patterns, which drive morphological, physiological, and biochemical changes ( [142]; reviewed by [166]).…”

Section: Causes Of Astrogliosismentioning

confidence: 99%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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“…; Romano et al. ), yet medium‐chain fatty acids (MCFA) can be metabolised as an additional energy substrate in both glial cells and neurons (Augustin et al. ) (Fig.…”

Section: Energy Metabolism In the Developing And Adult Brainmentioning

confidence: 99%

The potential contribution of impaired brain glucose metabolism to congenital Zika syndrome

et al. 2019

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The Zika virus (ZIKV) became a major worldwide public concern in 2015 due to the congenital syndrome which presents the highest risk during the first trimester of pregnancy and includes microcephaly and eye malformations. Several cellular, genetic and molecular studies have shown alterations in metabolic pathways, endoplasmic reticulum (ER) stress, immunity and dysregulation of RNA and energy metabolism both in vivo and in vitro. Here we summarise the main metabolic complications, with a particular focus on the possibility that brain energy metabolism is altered following ZIKV infection, contributing to developmental abnormalities. Brain energetic failure has been implicated in neurological conditions such as autism disorder and epilepsy, as well as in metabolic diseases with severe neurodevelopmental complications such as Glut‐1 deficiency syndrome. Therefore, these energetic alterations are of wide‐ranging interest as they might be directly implicated in congenital ZIKV syndrome. Data showing increased glycolysis during ZIKV infection, presumably required for viral replication, might support the idea that the virus can cause energetic stress in the developing brain cells. Consequences may include neuroinflammation, cell cycle dysregulation and cell death. Ketone bodies are non‐glycolytic brain fuels that are produced during neonatal life, starvation or fasting, ingestion of high‐fat low‐carbohydrate diets, and following supplementation with ketone esters. We propose that dietary ketones might alter the course of the disease and could even provide some degree of prevention of ZIKV‐associated abnormalities and potentially related neurological conditions characterised by brain glucose impairment.

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Fats for thoughts: An update on brain fatty acid metabolism

Cited by 88 publications

References 47 publications

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

The potential contribution of impaired brain glucose metabolism to congenital Zika syndrome

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