New study uncovers an intriguing liver–brain connection

A new study published in the Journal of Physiology reveals that ketone production in the liver plays a critical role in maintaining brain health, especially during physical activity. Researchers at the University of Missouri found that when liver cells were unable to produce ketones, rats showed impaired memory and reduced mitochondrial function in the brain. However, regular endurance exercise was able to reverse these negative effects, restoring cognitive performance and mitochondrial health. These findings offer new insights into how liver metabolism supports the brain.

Scientists have long known that exercise improves cognitive function and helps protect the brain from aging and disease. This benefit has been linked to increased neurogenesis, synaptic plasticity, and improvements in mitochondrial health.

One proposed contributor to these effects is ketone bodies—molecules produced by the liver during fasting or physical exertion, which can serve as an alternative energy source for the brain. The most abundant of these, beta-hydroxybutyrate, has been shown to reduce oxidative stress, enhance mitochondrial respiration, and promote synaptic plasticity. Despite this, the direct role of liver-derived ketones in mediating the cognitive effects of exercise has not been fully explored.

“The liver makes ketones as an alternative fuel source, especially during exercise. Since it is known that both exercise and ketones are good for brain health, we wanted to find out if exercise helps the brain by increasing ketones. This could lead to new ways to protect against brain diseases like Alzheimer’s disease,” explained Professor R. Scott Rector and postdoctoral researcher Taylor Kelty.

To address this gap, the researchers used a viral technique to reduce the expression of a key enzyme involved in ketone production—3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2)—in the livers of healthy, 6-month-old female rats. This enzyme catalyzes the first step in ketogenesis. By knocking it down, the researchers were able to investigate what happens to the brain when the liver can no longer produce ketones during exercise.

The rats were divided into several groups. Some were sedentary, while others performed either a single bout of treadmill running or a 4-week endurance training program. The team measured blood ketone levels, isolated mitochondria from the frontal cortex, conducted protein analyses of brain tissue, and tested the animals’ spatial memory using a Y-maze. Additional in vitro experiments were conducted on neuronal cells to assess mitochondrial respiration following genetic manipulation of ketone metabolism.

The results showed that both acute and chronic exercise elevated ketone levels in the bloodstream one hour and 48 hours after activity, respectively. However, in rats with liver-specific knockdown of HMGCS2, these increases were significantly blunted. This confirmed that HMGCS2 is necessary for producing the rise in circulating ketones that typically follows exercise.

When the researchers looked at the brain, they found that the absence of liver ketone production led to widespread dysfunction in the frontal cortex, particularly in mitochondrial processes. Proteomic analyses revealed increased markers of mitochondrial dysfunction, decreased activity in pathways related to oxidative phosphorylation and energy production, and reduced expression of proteins involved in synaptic plasticity. Mitochondria isolated from the brains of these rats showed impaired respiration, especially in the energy-producing complexes of the electron transport chain.

Cognitively, rats with HMGCS2 knockdown showed deficits in spatial memory. In the Y-maze test, they spent significantly less time exploring the novel arm of the maze, a sign of impaired memory performance. Notably, these impairments occurred even in the absence of neurodegenerative disease, suggesting that reduced liver ketone production alone can disrupt brain function.

“Our study found the body’s natural production of ketones is important for keeping the brain healthy. It helps maintain memory, learning abilities, and the health of the brain’s energy factories (mitochondria),” Scott and Kelty told PsyPost.

But one of the most striking findings came from the exercise-trained rats. Despite the deficiency in liver ketone production, those who underwent four weeks of endurance training showed normal cognitive performance and restored mitochondrial function in the brain. Their proteomic signatures also revealed elevated markers of synaptic plasticity, including pathways related to long-term potentiation and synaptogenesis. In other words, exercise compensated for the loss of liver ketones and reversed the associated brain impairments.

“We also found that exercise can still protect the brain, even when the liver’s ability to make ketones is suppressed, which may be relevant to those with liver disease that causes reduced ketone production,” the authors explained.

To test whether similar effects occurred at the cellular level, the researchers conducted experiments on PC12 cells—neuronal-like cells derived from rats. By knocking down an enzyme required for ketone oxidation in these cells, they observed reductions in mitochondrial respiration, mirroring the in vivo findings. These results support the idea that the brain relies not just on the presence of ketones, but also on the ability of neurons to use them for energy.

The study offers several novel insights. First, it demonstrates that liver ketone production during exercise is not just a metabolic side effect—it plays a key role in brain health. Second, it shows that even when ketone production is impaired, exercise can still rescue brain function, possibly through alternative pathways involving other exercise-induced molecules. Finally, it establishes a direct mechanistic link between liver metabolism and brain mitochondrial performance, suggesting that disruptions in liver function could contribute to cognitive decline.

“We originally thought that liver making ketones was a primary reason exercise helps the brain,” Scott and Kelty noted. “We expected that if ketone production was reduced during exercise, brain health would be compromised. However, it seems exercise activates backup pathways that enhance brain health even when ketone production is reduced.”

But there are some limitations to note. The study focused exclusively on female rats, and the results may not fully generalize to males or humans. The cognitive testing relied primarily on the Y-maze, which may be less sensitive to improvements in cognition than to deficits. Additionally, while the knockdown of HMGCS2 reduced ketone levels, it did not eliminate them entirely, leaving open the possibility that other sources of ketones or compensatory mechanisms were at play. Finally, the precise molecular signals by which exercise bypasses the need for liver ketone production remain unknown.

The researchers hope future studies will investigate how these findings apply to conditions like Alzheimer’s disease, where both liver dysfunction and mitochondrial impairments have been observed. They also suggest that strategies aimed at increasing liver ketone production—or enhancing the brain’s ability to use ketones—could offer a new path for preventing or treating neurodegenerative disorders.

“Our findings suggest that taking care of the liver and understanding ketone metabolism could be a new way to help prevent or slow down brain diseases,” the authors noted. “This study highlights how important exercise is for brain health — especially for people who might have lower ketone production due to liver conditions like Steatotic Liver Disease.”

The study, “Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise,” was authored by Taylor J. Kelty, Nathan R. Kerr, Chih H. Chou, Grace E. Shryack, Christopher L. Taylor, Alexa A. Krause, Alexandra R. Knutson, Josh Bunten, Tom E. Childs, Grace M. Meers, Ryan J. Dashek, Patrycja Puchalska, Peter A. Crawford, John P. Thyfault, Frank W. Booth, and R. Scott Rector.