Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

Abstract

It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,[7][8][9][10][11][12][13] C 3 ]heptanoate was examined in the normal mouse brain and in G1D by 13 C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13 C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13 C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucosedeficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

“…Dysregulation of this gene leads to autosomal recessive disorder of neutral lipid storage disease with myopathy (NLSD-M) (Tavian et al, 2012). As brain also metabolizes fatty acid as a source of energy (Marin-Valencia et al, 2013), the overexpression of PNPLA2 induced by Aloe emodin could plays a role in positive regulation of lipid metabolism in glioblastoma patients. SCAP is a regulatory element binding protein (SREBP) cleavage-activating protein (SCAP).…”

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

“…4 Heptanoate metabolism appears to maintain glycolysis and not inhibit phosphofructokinase activity in healthy tissue, most likely because it is gluconeogenic and anaplerotic. 25 When [3,4,5-13 C] heptanoate was provided though intracarotid infusion, which provided 50% of caloric requirements, most of the labeling derived from heptanoate was found in glutamine, again indicating that MCTs are metabolized primarily in astrocytes. As astrocytic end feet surround the capillaries, it can be proposed that heptanoate would be mostly taken up into the astrocytes, where through the propionyl-CoA carboxylation pathway or through metabolism to acetyl-CoA, it can enter the TCA cycle.…”

“Brain steatosis” in an obese mouse model during cycles of Famine and Feast the underestimated role of fat (WAT) in brain volume formation

“…The metabolic effects of randomized fats, has been sparsely studied in humans, and literature data to date is mostly confined to rodent studies [17,18,21].…”

“…Like we earlier described for the liver the observation of hepatic steatosis during conditions of "feast" and "famine" [2] -as an evolutionary paradox [2]-, starvation resulted also in this study in a "brain steatosis'' which can be explained for the starvation group by the essential decline of Phoshophatidylcholine (PC) -the major constituent of the neuron-resulting in significant increase of Lysophosphatidylcholine (LysoPC) a preferred carrier as byproduct of PUFAs across the blood-brain barrier [16] (Tabel 1). In addition, several studies with rodent models are indicative that FA can traverse the Blood Brain Barrier (BBB) [17,18]. In studying High-Fat (HF) diet induced obesity, Insuline Resistance (IR) and type 2 diabetes (T2DM) by lipidomics based LC-MS techniques using a Systems Biology approach, we found unexpectedly a non-significant increase of 1000% up to >10,000% of several Triacylglycerol compounds [6], which we further indicated in this C57BL6 mouse model as "overgrown brain".…”

“…So from our observations we can conclude for a juvenile rodent study in a by bovine lard induced obesity model it shows an "overgrown brain" mainly by the accumulation of triacylglycerols (TGs) based on high amounts of unsaturated C:50-1; C50-2; C:52-2; C:52-3; C54-3;C:54-4 and C56-3 TGs. In addition "brain steatosis" in the HF-diet group was also caused by a non-significant 135% increase of Docosahexaenoic Acid ([DHA] C22:6Ω3) in the HF-diet group in the brain (Table 3) [15][16][17][18][19][20].…”