The Surprising Link Between Liver, Exercise, and Memory

Physical exercise, such as running, helps protect the brain, and this may be linked to the production of ketones by the liver. A study on rats showed that when the liver is unable to produce these ketones, there are losses in memory and in the health of brain cells. However, regular exercise was able to prevent this damage, even with low production of ketones. This reinforces how the body and brain are connected, and how staying active is essential for mental health.

We know that practicing physical exercise has many benefits for the body and mind. A specific type of exercise, called resistance exercise (such as running or cycling), has already been shown in several studies to be protective for the brain, that is, it helps to maintain brain health and can even reduce the risk of neurological diseases.

However, there are still doubts about exactly how these benefits occur. One hypothesis is that the liver, during exercise, produces substances called ketones that could be involved in this protection of the brain.

To better understand the role of liver ketones in brain health, researchers used a virus to block an enzyme in the liver called HMGCS2, which is essential for ketone production, in healthy 6-month-old female rats.

The animals were then divided into groups: some did only a short, isolated bout of exercise, while others underwent a longer, 4-week training run.

After the exercise, the researchers measured blood ketone levels, tested memory and behavior, and examined the rats’ brains.

Acute exercise (done just once) increased blood ketones, but when ketone production in the liver was blocked, this increase disappeared, both after the single exercise and after the 4-week program.

In the brain, the effects were also clear: when ketone production was stopped, the function of mitochondria (the “power plants” of cells) worsened, especially in a key region called the frontal cortex.

In addition, the rats with fewer ketones had poorer spatial memory and less adaptability between neurons, which impairs learning.

This image shows the impact of reduced liver ketone production on brain function, and how exercise can reverse this. On the left, we see a mouse with the HMGCS2 enzyme “silenced” in the liver, which reduces the production of ketone bodies (such as BHB and AcAc). This drop in ketones impairs the functioning of mitochondria in the brain, reduces the production of BDNF (essential for the health of neurons), hinders synaptic plasticity (the ability to form new neural connections) and, ultimately, impairs cognition. On the right, even with reduced HMGCS2, resistance exercise (such as running on a treadmill) restores all of these functions: it improves mitochondrial function, increases BDNF, improves synaptic plasticity and preserves cognition. In short, exercise acts as a “compensation” for the negative effects caused by low liver ketone production.

Interestingly, even when ketones were low, long-term exercise training was able to prevent these losses. In other words, resistance exercise helped protect the brain, even when fewer ketones were being produced by the liver.

This study was the first to show that ketone production by the liver is important for maintaining brain health, especially in terms of memory and cellular energy.

It also reinforces the value of regular exercise as a powerful way to protect the brain, even when other bodily functions, such as the liver, are not functioning optimally. In short, taking care of your body (and your liver) has a direct impact on how your mind functions.

READ MORE:

Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise

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

The Journal of Physiology. 14 January 2025

DOI: 10.1113/JP287573

Abstract:

Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4 weeks of chronic treadmill running (5 days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1 h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1 h after acute exercise and 48 h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1 h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I + II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health.