Why does Brain Metabolism not Favor Burning of Fatty Acids to Provide Energy? - Reflections on Disadvantages of the Use of Free Fatty Acids as Fuel for Brain

Abstract

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to b-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) b-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the b-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. Keywords: ATP generation; fatty acid; mitochondria; neural cells; oxidative stress Journal of Cerebral Blood BRAIN ENERGY METABOLISM AT A GLANCEThe minor utilization of the energy-rich long-chain fatty acids in brain energy metabolism has not been well understood. Interestingly, other organs with high energy turnover, such as the heart and kidney, largely oxidize fatty acids. The low fatty acid oxidation in the brain might be explained in terms of (i) a slow passage of fatty acids across the blood-brain barrier (BBB), (ii) a low enzymatic capacity for the fatty acid degradation and, (iii) detrimental side effects of long-chain fatty acids in the nonesterified or activated form on the mitochondrial ATP synthesis and/or on the equilibrium between the generation and the disposal of reactive oxygen species (ROS). Before going into the detailed analysis, a brief summary of the brain energy metabolism will be given.The high ATP demand in the brain tissue is impressively illustrated by the following numbers: the human brain accounts for B2% of the body mass, but consumes 20% of the total oxygen consumed by the whole body. Among the neural cells, neurons demand for most of the energy, whereas the energy consumption of astrocytes contributes to only B5% to 15% of the total energy requirement of the brain. This fact, together with the analysis of metabolites profiles supports the view that the energy metabolism of neurons is mainly aerobic and that of astrocytes mainly anaerobic glycolysis. Moreover, the largest portion of the ATP turnover occurs in the gray matter of the brain, which has a high density of excitatory glutamatergic synapses.1,2 For the rodent brain, it has been estimated that B80% of ...

On the Futile Existence of DHA, None of EPA and the Predominant Role of the Triacylglycerols (TGs) in the Post Mortem Human Brain: An LCMS Study with Evolutionary Implications

“…But probably many other compounds of mainly the Cholesteryl fraction (PUFAs) are involved, and for this reasoning we will elucidate this topic related to optional passive/active carriers in the BBB. Recently, the opinion is contradicted that Very Long Chain Fatty Acids (VLCFA) can pass the BBB to fuel the brain [14]. Our findings are opposite and give awareness of a predominant role of the TGs.…”

“…If we eliminate this peak a whole range smaller C:46-C:60 TGs lipid molecules are possibly fueling the brain according to our observations. These are in contrast towards the theories of considering the ability of VLCFA to fuel the brain [14]. Following our "membrane" approach the transporter for "fishy" PUFA, DHA is not detected which is in contrast to the research of the studies of Nguyen et al; Ben-Zvi et al; Guemez-Gamboa et al [4,16,17], focusses on the Mfsd2a protein as "leaky position" in the BBB for the "fishy" omega-3 DHA.…”

“…The PUFAs (≈Cholesterylesters) take an important place (13.61%) as well as their carriers the LPC lipid compound (5.64%) [13][14][15][16]. Interestingly, both omega-3 "fish oil" FA EPA and DHA are found in rather high concentrations respectively 0.277% and 0.258% respectively in blood plasma but not in the brain.…”

Dietary carnosic acid, selenized yeast, selenate and fish oil affected the concentration of fatty acids, tocopherols, cholesterol and aldehydes in the brains of lambs

“…It has been found (Table 4) that the brains of all examined lambs are characterized by the high concentration of LPUFAs (∼ 25 % of FAs), especially DHA (11-13 % of FAs). In fact, lipids in central nervous tissues of mammals are characterized by a high concentration of DHA, which is especially enriched in amino-phospholipids, serine phosphoglycerides, and ethanol-amine (Schönfeld and Reiser, 2013).…”

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism

“…Cholesterol levels are tightly controlled by sterol regulatory element-binding protein 2 (SREBP2), the major transcription factor regulating cholesterol synthetic genes (2). In contrast to fatty acids, which are in equilibrium with the rest of the body, nearly all brain cholesterol is synthesized in the brain because cholesterol-carrying lipoproteins, with the exception of some very dense HDL, cannot readily cross the blood-brain barrier (3)(4)(5).…”