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A study on mice fed a high-fat fructose diet to induce a condition resembling non-alcoholic fatty liver disease in humans suggests that liver damage from this diet triggers neuroinflammation and anxiety-like behaviors by disrupting communication between the liver and the brain. The research was published in Psychopharmacology.
Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat builds up in the liver of individuals who consume little or no alcohol. It has become one of the most common liver disorders worldwide and is associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD can range from simple steatosis (fat accumulation without inflammation) to non-alcoholic steatohepatitis, which involves liver inflammation and can progress to fibrosis or cirrhosis—the most severe stages of liver damage.
Many people with NAFLD have no symptoms, although some may experience fatigue, discomfort in the upper right abdomen, or mild liver enlargement. The exact cause of NAFLD remains unclear, but insulin resistance, poor diet, and physical inactivity are considered major risk factors.
Currently, lifestyle changes such as weight loss, healthy eating, and regular exercise are the primary treatments, as no specific medications for NAFLD have been approved. Without intervention, the disease can increase the risk of liver failure, cardiovascular disease, and liver cancer. Prevention strategies focus on maintaining a healthy weight, managing blood sugar, and limiting processed foods and added sugars.
Study author Hongmei Du and colleagues aimed to explore the relationship and underlying mechanism between liver injury caused by a high-fat fructose diet and the emergence of anxiety-like behaviors in mice. They also sought to determine whether corilagin—a natural compound with hepatoprotective properties—could mitigate the behavioral and physiological effects of liver injury.
Corilagin is an ellagitannin (a type of hydrolysable tannin) found in various medicinal plants. It is one of the main phenolic compounds in longan fruit (Dimocarpus longan), especially concentrated in the seed and pericarp. Prior research has shown that corilagin can reverse fatty liver changes in mice by reducing blood lipid levels, hepatic lipid accumulation, and abnormal lipid metabolism.
In this study, 26 male mice were randomly assigned to three groups. The first group received a standard diet. The second group was fed a high-fat diet and given 12.5% fructose syrup as drinking water to induce NAFLD. The third group received the same high-fat fructose diet along with intraperitoneal injections of corilagin every other day (2.5 mg/kg).
To test whether corilagin had direct effects on anxiety independent of liver damage, the researchers also established four additional groups with another 27 mice. One group was fed a normal diet, the second received corilagin while on a normal diet, the third was exposed to chronic social defeat stress (CSDS) to induce anxiety-like behavior, and the fourth received corilagin during CSDS exposure. Importantly, the CSDS model induces anxiety symptoms through social stress rather than metabolic damage, allowing the researchers to isolate liver-dependent effects.
After these treatments, all mice underwent a battery of behavioral tests to assess anxiety-like behavior. Researchers then conducted biochemical analyses on blood and brain tissue to assess inflammation and glutamate levels.
The results showed that mice fed the high-fat fructose diet developed anxiety-like behaviors, along with elevated levels of fat and glutamate in the blood. They also developed liver damage, with fat accumulation in hepatic tissue and elevated levels of liver injury markers (ALT and AST). In addition, inflammation markers—including IL-6, IL-1β, and TNF-α—were elevated not only in the liver but also in the hippocampus and cortex, suggesting that liver damage triggered neuroinflammation.
Treatment with corilagin alleviated these physiological and behavioral changes. It reduced hepatic fat accumulation, normalized glutamate levels in the blood and brain, lowered inflammatory markers, and reduced anxiety-like behaviors in the mice fed the high-fat fructose diet.
However, when anxiety-like behavior was induced through chronic social defeat stress in mice without liver damage, corilagin did not improve symptoms. This suggests that its behavioral benefits are tied to its ability to protect liver function and prevent downstream effects on the brain, rather than a direct anxiolytic effect.
“Our results indicated that the HFFD-induced NAFLD [high-fat fructose diet-induced non-alcoholic fatty liver disease] and mild hepatic fibrosis led to elevated levels of glutamate and aminotransferases, which infiltrated the brain, causing inflammation, and subsequently induced anxiety-like behaviors in mice. These pathological and behavioral manifestations were ameliorated through corilagin intervention. This study provides a possible underlying mechanism between HFFD and neurological disorders,” the study authors concluded.
The study sheds light on the effects of liver damage caused by the non-alcoholic fatty liver disease on brain and mental health. However, it should be noted that this was a study on mice, not on humans. While mice and humans share many physiological similarities, they are still very different species. Results on humans might not be identical.
The paper, “High-fat Fructose diet induces neuroinflammation and anxiety-like behaviors by modulating liver-brain axis communication,” was authored by Hongmei Du, Yuan Zhou, Jia Wang, Xianbing Bai, Borui Tao, and Ming Chen.
