Thermodynamic Analysis to Evaluate the Effect of Diet on Brain Glucose Metabolism: The Case of Fish Oil

Abstract

Inefficient glucose metabolism and decreased ATP production in the brain are linked to ageing, cognitive decline, and neurodegenerative diseases (NDDs). This study employed thermodynamic analysis to assess the effect of fish oil supplementation on glucose metabolism in ageing brains. Data from previous studies on glucose metabolism in the aged human brain and grey mouse lemur brains were examined. The results demonstrated that Omega-3 fish oil supplementation in grey mouse lemurs increased entropy generation and decreased Gibbs free energy across all brain regions. Specifically, there was a 47.4% increase in entropy generation and a 47.4 decrease in Gibbs free energy in the whole brain, indicating improved metabolic efficiency. In the human model, looking at the specific brain regions, supplementation with Omega-3 polyunsaturated fatty acids (n-3 PUFAs) reduced the entropy generation difference between elderly and young individuals in the cerebellum and particular parts of the brain cortex, namely the anterior cingulate and occipital lobe, with 100%, 14.29%, and 20% reductions, respectively. The Gibbs free energy difference was reduced only in the anterior cingulate by 60.64%. This research underscores that the application of thermodynamics is a comparable and powerful tool in comprehending the dynamics and metabolic intricacies within the brain.

Keywords: Gibbs free energy; brain ageing; brain glucose metabolism; entropy; fish oil supplementation; n-3 PUFAs.

Figure 1

Glucose transporters (GLUTs) play a crucial role in facilitating the transportation of glucose from capillaries to neurons and astrocytes. Once inside the cells, the glycolytic pathway undergoes breakdown through the glycolytic pathway, forming glucose into pyruvate and yielding a net of two ATP molecules per glucose molecule. Further metabolic processes take place within the mitochondria, where pyruvate is subjected to oxidative metabolism via the tricarboxylic acid (TCA) cycle. The TCA cycle generates approximately 30 or 36 ATP molecules. The glyceraldehyde-3-phosphate dehydrogenase reaction catalyses a pivotal step in converting glucose to pyruvate. This reaction involves the regeneration of NAD+ from NADH, a coenzyme produced during the reaction. The malate aspartate shuttle (MAS) facilitates the transfer of cytoplasmic NADH to the mitochondria, where it is oxidized through the electron transport chain (ETC). However, under specific conditions such as hypoxia or anoxia, pyruvate can be converted to lactate through the lactate dehydrogenase (LDH) reaction. Lactate accumulation inside cells triggers a reversal of the LDH reaction. Monocarboxylic acid transporters (MCT) come into play to release lactate from the cell. This process eliminates pyruvate as an oxidizable substrate for the cell and limits the ATP yield per glucose to two. In the excitatory neuronal activity, glutamate (Glu) is released, and a significant portion is absorbed through GLT-1 in astrocytes. This activation of GLT-1 stimulates Na+/K+-ATPase, subsequently triggering aerobic glycolysis. The metabolic analogue of glucose, 2-deoxyglucose (2-DG), is metabolized by hexokinase, similar to its ¹⁸F analogue used in PET. However, further metabolism is halted at this stage, resulting in the trapping of radioactivity in the form of 2-DG-6-phosphate (2-DG-6P), the signal detected by PET. Adapted from [4,5,6,7].

Figure 2

Graphical demonstration of a healthy brain as an open thermodynamic system.