Mindful Eating: A Deep Insight Into Fructose Metabolism and Its Effects on Appetite Regulation and Brain Function

Abstract

Fructose, a common sweetener in modern diets, has profound effects on both metabolism and brain function, primarily due to its distinct metabolic pathways. Unlike glucose, fructose bypasses critical regulatory steps in metabolism, particularly the phosphofructokinase-1 (PFK-1) feedback inhibition, leading to uncontrolled metabolism and increased fat storage. This review delves into the metabolic consequences of fructose consumption, including its limited role in directly stimulating insulin secretion, which affects satiety signaling and contributes to increased food intake. The small intestine initially helps metabolize ingested fructose, shielding the liver and brain from excessive exposure. However, when consumed in excess, particularly in diets high in processed foods, this protective mechanism becomes overwhelmed, contributing to metabolic disorders such as insulin resistance, obesity, and fatty liver disease. The review also explores fructose's impact on the brain, with a focus on the hippocampus, a key region for memory and learning. Chronic high fructose intake has been linked to mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and neuroinflammation, all of which contribute to cognitive decline and impairments in memory and learning. Additionally, fructose-induced alterations in insulin signaling in the brain are associated with increased risk for neurodegenerative diseases. These findings underscore the potential long-term neurological consequences of excessive fructose intake and highlight the need for further human studies to assess the full spectrum of its effects on brain health. Addressing the rising consumption of fructose, particularly in processed foods, is essential for developing targeted strategies to mitigate its adverse metabolic and cognitive outcomes.

Keywords: appetite; brain; fructose; fructose metabolism; high-fructose diet; hypothalamus; neuroinflammation.

Figure 1

Comparative metabolism of fructose and glucose. ALT = alanine transaminase, LDH = lactate dehydrogenase, PC = pyruvate carboxylase, PDH = pyruvate dehydrogenase, PFK-1 = phosphofructokinase-1, TCA = tricarboxylic acid cycle.

Figure 2

Intestinal absorption of fructose. Fructose molecules (F) from the intestinal lumen are transported across the apical membrane by GLUT5 transporters. Once inside the intestinal cell, fructose is phosphorylated by the enzyme ketohexokinase (KHK) to fructose-1-phosphate and its respective fructose metabolites (FM). Some of the fructose molecules are also channeled directly into the bloodstream through the GLUT2 transporters located at the basolateral membrane, highlighting the dual pathway of fructose absorption.

Figure 3

Differential fructose absorption in normal vs. ChREBP KO Mice. F = fructose, FM = fructose metabolites.

Figure 4

Effects of fructose vs. glucose intake on satiety and metabolic pathways and energy regulators. Effects ACC = acetyl-CoA carboxylase, AgRP = agouti-related peptide, CART = cocaine- and amphetamine-related transcript, NPY = neuropeptide Y, POMC = pro-opiomelanocortin.

Figure 5

Differential effects of glucose and fructose intake on satiety, hedonic reward, and metabolic pathways. AMPK, AMP-activated protein kinase; NPY, neuropeptide Y; AgRP, agouti-related peptide; POMC, Pro-opiomelanocortin; CART, cocaine- and amphetamine-regulated transcript; GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide; PYY, peptide YY.