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Energy Contribution of Octanoate to Intact Rat Brain Metabol

Edward

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Apr 20, 2013
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Energy Contribution of Octanoate to Intact Rat Brain Metabolism Measured by 13C Nuclear Magnetic Resonance Spectroscopy
https://docs.google.com/file/d/0B1wyy-gxfSdsSWJFV2k2bEVlNkU/edit?usp=sharing

Glucose is the dominant oxidative fuel for brain, but studies have indicated that fatty acids are used by brain as well. We postulated that fatty acid oxidation in brain could contribute significantly to overall energy usage and account for non-glucose-derived energy production. [2,4,6,8-13C4]octanoate oxidation in intact rats was determined by nuclear magnetic resonance spectroscopy. We found that oxidation of 13C-octanoate in brain is avid and contributes approximately 20% to total brain oxidative energy production. Labeling patterns of glutamate and glutamine were distinct, and analysis of these metabolites indicated compartmentalized oxidation of octanoate in brain. Examination of liver and blood spectra revealed that label from 13C-octanoate was incorporated into glucose and ketones, which enabled calculation of its overall energy contribution to brain metabolism: glucose (predominantly unlabeled) and 13C-labeled octanoate can account for the entire oxidative metabolism of brain. Additionally, flux through anaplerotic pathways relative to tricarboxylic acid cycle flux (Y) was calculated to be 0.08 +/- 0.039 in brain, indicating that anaplerotic flux is significant and should be considered when assessing brain metabolism. Y was associated with the glutamine synthesis compartment, consistent with the view that anaplerotic flux occurs primarily in astrocytes.

Brain uptake and metabolism of [1-11C]octanoate in rats: pharmacokinetic basis for its application as a radiopharmaceutical for studying brain fatty acid metabolism
https://docs.google.com/file/d/0B1wyy-gxfSdsNFBXaVJ4VDVpcVE/edit?usp=sharing

The uptake of octanoate in rat brain and its metabolism were investigated by means of intravenously injecting [1-11C] or [1-14C]octanoate as a tracer. The radioactivity in the cerebrum was increased by an injection of [1-11C]octanoate, and reached its peak level (0.33% ID/g) in about 2 to 5 min, and then decreased slowly. The cerebrum-to-blood ratio of the radioactivity increased with time over a period of 30 min. At 30 sec, [1-11C]octanoate that remained unchanged in the cerebrum accounted for only 8% of the total radioactivity, in spite of there being about 90% in the blood. By means of an injection of [1-14C]octanoate, more than 70% of the total radioactivity in the cerebrum was found to be attributable to radiolabeled glutamate and glutamine at each time point measured between 30 sec and 30 min. The results show that [1-11C]octanoate enters rat brain easily and is trapped in the cerebrum, probably in the form of glutamate and glutamine, and the usefulness of [1-11C]octanoate as a radiopharmaceutical for studying brain fatty acid metabolism by positron emission tomography is therefore suggested.

Axons need glial peroxisomes
https://docs.google.com/file/d/0B1wyy-gxfSdsWGVVa3Q1ZldDVjg/edit?usp=sharing

Several devastating genetic diseases illustrate that peroxisomes are essential to the development and functioning of the central nervous system. New work using a mouse model now shows that peroxisome integrity in oligodendrocytes is essential for axonal maintenance.

Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocyte
https://docs.google.com/file/d/0B1wyy-gxfSdsb1Z5cFl2Z1N6VlE/edit?usp=sharing

Oligodendrocytes myelinate axons for rapid impulse conduction and contribute to normal axonal functions in the central nervous system. In multiple sclerosis, demyelination is caused by autoimmune attacks, but the role of oligodendroglial cells in disease progression and axon degeneration is unclear. Here we show that oligodendrocytes harbor peroxisomes whose function is essential for maintaining white matter tracts throughout adult life. By selectively inactivating the import factor PEX5 in myelinating glia, we generated mutant mice that developed normally, but within several months showed ataxia, tremor and premature death. Absence of functional peroxisomes from oligodendrocytes caused widespread axonal degeneration and progressive subcortical demyelination, but did not interfere with glial survival. Moreover, it caused a strong proinflammatory milieu and, unexpectedly, the infiltration of B and activated CD8+ T cells into brain lesions. We conclude that peroxisomes provide oligodendrocytes with an essential neuroprotective function against axon degeneration and neuroinflammation, which is relevant for human demyelinating diseases.

Oligodendroglial impact on axonal function and survival - a hypothesis
http://journals.lww.com/co-neurolog...droglial_impact_on_axonal_function_and.4.aspx

Purpose of review: Although multiple sclerosis is considered the prototype of a primary autoimmune disease in the central nervous system, there is emerging evidence that primary oligodendrocyte dysfunctions can suffice to trigger a secondary immune response in the nervous system. This short review focuses on the possible primary role of oligodendrocytes in axon loss and inflammatory demyelination.

Recent findings: The analysis of natural and engineered mouse mutants has provided unexpected insight into oligodendrocyte function beyond that of axonal myelination for rapid impulse propagation. Specifically, mutations in some genes thought to be required for myelin assembly revealed an additional role of oligodendrocytes in supporting long-term axonal function and survival. Other mutations have been reported that cause both central nervous system demyelination and neuroinflammation, with pathological features known from human leukodystrophy patients. In human multiple sclerosis, demyelination leads invariably to axon loss, but the underling pathomechanisms may not be restricted to that of a primary immune-mediated disorder.

Summary: Collectively, experimental and pathological findings point to a primary role of myelinating glia in long-term axonal support and suggest that defects of lipid metabolism in oligodendrocytes contribute to inflammatory myelin diseases.
 

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