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Specific regions of the brain are capable of fructose metabolism.

ABSTRACT: High fructose consumption in the Western diet correlates with disease states such as obesity and metabolic syndrome complications, including type II diabetes, chronic kidney disease, and non-alcoholic fatty acid liver disease. Liver and kidneys are responsible for metabolism of 40-60% of ingested fructose, while the physiological fate of the remaining fructose remains poorly understood. The primary metabolic pathway for fructose includes the fructose-transporting solute-like carrier transport proteins 2a (SLC2a or GLUT), including GLUT5 and GLUT9, ketohexokinase (KHK), and aldolase. Bioinformatic analysis of gene expression encoding these proteins (glut5, glut9, khk, and aldoC, respectively) identifies other organs capable of this fructose metabolism. This analysis predicts brain, lymphoreticular tissue, placenta, and reproductive tissues as possible additional organs for fructose metabolism. While expression of these genes is highest in liver, the brain is predicted to have expression levels of these genes similar to kidney. RNA in situ hybridization of coronal slices of adult mouse brains validate the in silico expression of glut5, glut9, khk, and aldoC, and show expression across many regions of the brain, with the most notable expression in the cerebellum, hippocampus, cortex, and olfactory bulb. Dissected samples of these brain regions show KHK and aldolase enzyme activity 5-10 times the concentration of that in liver. Furthermore, rates of fructose oxidation in these brain regions are 15-150 times that of liver slices, confirming the bioinformatics prediction and in situ hybridization data. This suggests that previously unappreciated regions across the brain can use fructose, in addition to glucose, for energy production.

SUBMITTER: Oppelt SA

PROVIDER: S-EPMC5420427 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Specific regions of the brain are capable of fructose metabolism.

Oppelt Sarah A SA Zhang Wanming W Tolan Dean R DR

Brain research 20161227

High fructose consumption in the Western diet correlates with disease states such as obesity and metabolic syndrome complications, including type II diabetes, chronic kidney disease, and non-alcoholic fatty acid liver disease. Liver and kidneys are responsible for metabolism of 40-60% of ingested fructose, while the physiological fate of the remaining fructose remains poorly understood. The primary metabolic pathway for fructose includes the fructose-transporting solute-like carrier transport pr ...[more]

PMID: 28034722

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Project description:Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance. Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety.To study neurophysiological factors that might underlie associations between fructose consumption and weight gain.Twenty healthy adult volunteers underwent 2 magnetic resonance imaging sessions at Yale University in conjunction with fructose or glucose drink ingestion in a blinded, random-order, crossover design.Relative changes in hypothalamic regional cerebral blood flow (CBF) after glucose or fructose ingestion. Secondary outcomes included whole-brain analyses to explore regional CBF changes, functional connectivity analysis to investigate correlations between the hypothalamus and other brain region responses, and hormone responses to fructose and glucose ingestion.There was a significantly greater reduction in hypothalamic CBF after glucose vs fructose ingestion (-5.45 vs 2.84 mL/g per minute, respectively; mean difference, 8.3 mL/g per minute [95% CI of mean difference, 1.87-14.70]; P = .01). Glucose ingestion (compared with baseline) increased functional connectivity between the hypothalamus and the thalamus and striatum. Fructose increased connectivity between the hypothalamus and thalamus but not the striatum. Regional CBF within the hypothalamus, thalamus, insula, anterior cingulate, and striatum (appetite and reward regions) was reduced after glucose ingestion compared with baseline (P < .05 significance threshold, family-wise error [FWE] whole-brain corrected). In contrast, fructose reduced regional CBF in the thalamus, hippocampus, posterior cingulate cortex, fusiform, and visual cortex (P < .05 significance threshold, FWE whole-brain corrected). In whole-brain voxel-level analyses, there were no significant differences between direct comparisons of fructose vs glucose sessions following correction for multiple comparisons. Fructose vs glucose ingestion resulted in lower peak levels of serum glucose (mean difference, 41.0 mg/dL [95% CI, 27.7-54.5]; P < .001), insulin (mean difference, 49.6 ?U/mL [95% CI, 38.2-61.1]; P < .001), and glucagon-like polypeptide 1 (mean difference, 2.1 pmol/L [95% CI, 0.9-3.2]; P = .01).In a series of exploratory analyses, consumption of fructose compared with glucose resulted in a distinct pattern of regional CBF and a smaller increase in systemic glucose, insulin, and glucagon-like polypeptide 1 levels.

Project description:Non-alcohol fatty liver disease (NAFLD) is a common disorder that has increased in prevalence 20-fold over the last three decades. It covers a spectrum of conditions resulting from excess lipid accumulation in the liver without alcohol abuse. Among all the risk factors, over-consumption of fructose has been repeatedly reported in both clinical and experimental studies to be highly associated with the development of NAFLD. However, studying in vivo systems is complicated, time consuming and expensive. A detailed kinetic model of fructose metabolism was constructed to investigate the metabolic mechanisms whereby fructose consumption can induce dyslipidaemia associated with NAFLD and to explore whether the pathological conditions can be reversed during the early stages of disease. The model contains biochemical components and reactions identified from the literature, including ~120 parameters, 25 variables, and 25 first order differential equations. Three scenarios were presented to demonstrate the behavior of the model. Scenario one predicts the acute effects of a change in carbohydrate input in lipid profiles. The results present progressive triglyceride accumulations in the liver and plasma for three diets. The rate of accumulation was greater in the fructose diet than that of the mixed or glucose only models. Scenario two explores the variability of metabolic reaction rate within the general population. Sensitivity analysis reveals that hepatic triglyceride concentration is most sensitive to the rate constant of pyruvate kinase and fructokinase. Scenario three tests the effect of one specific inhibitor that might be potentially administered. The simulations of fructokinase suppression provide a good model for potentially reversing simple steatosis induced by high fructose consumption, which can be corroborated by experimental studies. The predictions in these three scenarios suggest that the model is robust and it has sufficient detail to present the kinetic relationship between fructose and lipid in the liver.

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Specific regions of the brain are capable of fructose metabolism.

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Specific regions of the brain are capable of fructose metabolism.

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