High fructose diets impair brain function and appetite control, study shows

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Apr 30 2025

New research links high-fructose diets, especially from processed foods, to disrupted appetite signals and long-term brain changes, raising concerns for developing brains.

Review: Mindful Eating: A Deep Insight Into Fructose Metabolism and Its Effects on Appetite Regulation and Brain Function. Image Credit: Oleksandra Naumenko / Shutterstock

A recent review study published in the Journal of Nutrition and Metabolism reviewed the metabolic consequences of fructose intake and its effects on the brain.

Throughout evolution, mammals may have relied on the consumption and metabolism of excess fructose as a survival mechanism to store energy and ensure its availability during periods of scarcity. This suggests that high fructose intake leads to a state of low energy, characterized by reduced production and utilization of adenosine triphosphate (ATP), while also promoting hunger and encouraging further food-seeking behavior. Glycogenolysis, fatty acid oxidation, and lipolysis are inhibited to store fat and glycogen in the liver.

This survival mode is unique to fructose, as glucose has opposite effects. Glucose is a fuel for immediate energy demands, whereas fructose stores energy for future needs. However, with the increase in processed foods, sedentary lifestyles, and high-fructose diets in contemporary times, this once-beneficial process has detrimental effects. In this review, researchers investigated the impact of high fructose intake on the hippocampus and other brain regions involved in the appetite-reward system.

Importantly, the study noted that the effects of fructose may vary depending on age, with younger individuals, particularly during adolescence, being more vulnerable to the neurocognitive impacts due to ongoing brain development.

Fructose metabolism and transport

Fructose metabolism lacks the regulatory steps found in the glucose metabolic pathway. Dietary fructose is primarily absorbed in the small intestine via the GLUT5 transporter. The small intestine plays a crucial initial role, metabolizing a significant portion (up to 90% at physiological doses) of ingested fructose into other metabolites, such as glucose, thereby shielding the liver from excessive direct exposure to fructose. Once inside the cell, fructose is rapidly phosphorylated by fructokinase (KHK) to fructose-1-phosphate (F1P), bypassing the control of the key regulatory enzyme phosphofructokinase-1 (PFK-1). Without such feedback inhibition, F1P further catabolizes into glyceraldehyde and dihydroxyacetone phosphate (DHAP), which can ultimately be phosphorylated to form glyceraldehyde-3-phosphate (G3P).

Both G3P and DHAP can be converted to form free fatty acids, methylglyoxal, and triglycerides through de novo lipogenesis, or they can be catabolized into compounds such as oxalacetate, acetyl-CoA, and alanine in the downstream glycolytic pathway. The overproduction without feedback inhibition results in excess metabolic byproducts involved in triglyceride synthesis, fatty acid synthesis, and glycolysis, contributing to metabolic disturbances.

Excess fructose, particularly from high-dose consumption every day with processed foods and sugary drinks, overwhelms the small intestine's capacity. This unmetabolized fructose then passes through the GLUT2 transporter into the portal vein, reaching the liver, where it promotes fat formation, and potentially the colon, altering the gut microbiota. Small amounts can also affect the brain.

Metabolic effects: whole fruits vs. processed sources

Crucially, the review highlights that the metabolic effects of fructose depend heavily on its source. Fructose from whole fruits, consumed with fiber, vitamins, and antioxidants, is absorbed more slowly. The fiber helps regulate absorption, preventing rapid spikes in blood sugar and liver fat production, and contributes to overall metabolic benefits and reduced inflammation.

In contrast, fructose from sugar-sweetened beverages (SSBs) and fruit juices, lacking fiber, is absorbed rapidly. This rapid absorption overwhelms the small intestine, leading to increased liver exposure, enhanced de novo lipogenesis (fat production), hepatic fat accumulation, insulin resistance, and dyslipidemia. Studies have linked fructose from sugar-sweetened beverages (SSBs) and juice, but not whole fruit, to unfavorable biomarker profiles, including inflammatory markers and higher intrahepatic lipid content.

Brain regions involved in satiety and food intake

The hypothalamus plays a key role in food intake homeostasis, receiving signals from the gastrointestinal tract via the brainstem. Five hypothalamic nuclei, paraventricular, ventromedial, lateral, arcuate, and dorsomedial nuclei, have been associated with appetite regulation and food intake. Within the arcuate nucleus, first-order neurons serve as metabolic sensors, integrating peripheral signals and exerting antagonistic effects on food intake.

In particular, a subset of neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) projects their effects to second-order neurons within the paraventricular nucleus, thereby inducing orexigenic effects that stimulate appetite. Conversely, another group of neurons expressing cocaine and amphetamine-related transcript (CART) and pro-opiomelanocortin (POMC) project to second-order neurons in the lateral hypothalamic region, leading to anorexigenic effects or food intake inhibition.

The regulation of satiety and appetite involves a complex network of brain areas. It is also subject to the influences of hedonic rewards, such as food, environment, emotional state, and palatability. A meta-analysis revealed that the amygdala, insula, orbitofrontal cortex, and hippocampus were correlated with appetite regulators, whereas the caudate nucleus, hypothalamus, thalamus, anterior cingulate cortex, and putamen functioned as satiety regulators. The insula and orbitofrontal cortex appear to be involved in both.

Effects of fructose on hypothalamic energy regulators

Energy levels in the body regulate signals for hormones and neurons to be inhibited or activated. When lipid reserves are high in the body, levels of the leptin hormone increase. Leptin exerts an anorexigenic effect by inhibiting AgRP/NPY neurons and increasing POMC/CART neurons, thereby decreasing food intake. Likewise, insulin levels rise and exert anorexigenic effects after food intake. These hormones, along with gut peptides like GLP-1 (satiety) and ghrelin (hunger), regulate appetite.

In the case of excess energy, ATP levels increase, while adenosine monophosphate (AMP) levels decline. AMP activates AMP-activated protein kinase (AMPK). Therefore, high energy (low AMP) leads to AMPK inactivation (dephosphorylation). AMPK normally catalyzes the phosphorylation (inactivation) of acetyl-CoA carboxylase (ACC), a key enzyme in fatty acid synthesis. Thus, when AMPK is inactive (in a high-energy state), ACC is active (dephosphorylated). ACC activation is prominent during positive energy balance, especially in the hypothalamus, where it increases malonyl-CoA, a product of ACC, which suppresses food intake.

Various neuropeptides in the hypothalamus are expressed in response to malonyl-CoA levels. Leptin and insulin signals normally inhibit the activity of AMPK, contributing to appetite control. However, fructose has a limited ability to stimulate insulin and leptin. This lack of stimulation, combined with the rapid metabolism of fructose, which can potentially deplete ATP and increase AMP in hypothalamic cells, leads to AMPK activation. Active AMPK then inactivates ACC, reducing malonyl-CoA levels. Furthermore, fructose minimally excites anorexigenic POMC neurons while keeping orexigenic AgRP/NPY neuron signals active. This reduces satiety compared to glucose and increases food intake.

Excess fructose intake, neuroinflammation, and cognitive dysfunction

Fructose is significantly more reactive in forming advanced glycation end products (AGEs) than glucose, contributing to neuroinflammation and oxidative stress. Studies indicate that AGEs derived from fructose accumulate in hippocampal neurons, triggering inflammatory pathways (such as RAGE/NF-κB) that lead to reactive gliosis, mitochondrial dysfunction, and neuronal impairment, all of which are hallmarks of neurodegeneration. Increased uric acid production resulting from fructose metabolism can also induce inflammation in the hippocampus.

A study found that PGC1-α and COX2, transcriptional factors involved in mitochondrial biogenesis and energy synthesis, were negatively affected in the hippocampus after just one week of high-fructose consumption in animal models. This was independent of peripheral metabolic alterations, such as weight gain, challenging the notion that changes in the brain stem solely from peripheral alterations or metabolic syndrome. This suggests fructose can have direct, early negative impacts on the brain, particularly concerning during critical neurodevelopmental periods like childhood and adolescence.

Other studies have noted that high fructose intake decreases signaling through crucial brain receptors, such as the insulin receptor (INSR) and glucagon-like peptide-1 receptor (GLP-1R), in the hippocampus. Both receptors play key neuroprotective roles in memory, learning, and neuronal survival. These findings were based on animal models, and further validation in human studies is needed.

Although some animal studies suggest that certain effects on the brain, such as neuroinflammation or impaired signaling, may be partially reversible with dietary improvement, others show that long-term high-fructose exposure can cause persistent or irreversible changes, especially when initiated early in life.

Concluding remarks

In summary, the increasing prevalence of diets high in fructose poses significant health risks due to its rapid and unregulated metabolism, which perpetuates a cycle of upregulation of its metabolic pathways and food-seeking behavior. The source of fructose significantly impacts its metabolic fate, with processed sources posing greater risks than whole fruits. High fructose intake for prolonged periods may cause brain alterations associated with insulin signaling, neurogenesis, neuroinflammation, and mitochondrial dysfunction, which could be initial contributors to cognitive impairment and neurodegenerative diseases. The review concludes with a call for increased public health awareness, particularly regarding dietary patterns in children and adolescents. It emphasizes the need for additional human clinical studies to elucidate the long-term effects across various life stages.