Study suggests the liver ‘remembers’ exercise

For millions of people who have stepped away from regular exercise because of injury, illness, pregnancy or the demands of daily life, returning to fitness can feel like starting from scratch. New research suggests that may not be the case.

A new study, “Endurance Exercise Elicits a Hepatic Memory Associated with Improved Metabolic Function and Protein Secretion,” provides evidence that the liver retains a biological “memory” of previous exercise, allowing the body to respond more effectively when physical activity resumes. The findings, led by University of Illinois Health and Kinesiology Assistant Professor Diego Hernandez-Saavedra, point to a previously unknown adaptation in the liver that could reshape scientists’ understanding of exercise, metabolism and chronic disease prevention.

The research expands on earlier work showing that skeletal muscle can retain a memory of prior exercise. This study is among the first to demonstrate that another major metabolic organ—the liver—also appears to preserve molecular changes after periods of regular physical activity.

Funding for the study came from the Center on Health, Aging and Disability in the College of Applied Health Sciences as well as the Campus Research Board.

“Our study shows that exercise can help our body be healthier, specifically our liver, and that those ‘memories’ that we stored from the time we exercised can help us stay healthy over time,” said Hernandez-Saavedra, who is in AHS. “This is the first-of-its-kind study that shows that the whole body, not just the muscles, remembers exercise.”

The liver plays a central role in regulating blood sugar, processing fats and producing proteins that circulate throughout the body. During regular endurance exercise, liver cells activate genes that improve metabolic health. While many of those changes diminish when exercise stops, the study found the liver does not fully return to its pre-exercise state.

Instead, researchers discovered that the organ remains biologically “primed.” When exercise resumes, those dormant pathways reactivate more quickly and more powerfully than they did during initial training.

“If you had to explain this paper to someone in one sentence,” Hernandez-Saavedra said, “your liver remembers every workout you’ve ever done, and that memory makes getting back in shape faster, more effective, and more protective for your metabolic health than if you’d never exercised before.”

The majority of the mechanistic work was conducted in mice using carefully controlled endurance-training and detraining protocols. Researchers found that animals returning to exercise after a period of inactivity demonstrated stronger improvements in blood sugar regulation, reductions in liver fat and enhanced metabolic responses compared with animals exercising for the first time.

One of the study’s most striking discoveries involved a protein known as carboxylesterase 4A, or CES4A. The protein was secreted into the bloodstream only during retraining—not during an initial training program of equal duration—suggesting the liver distinguishes between first-time exercise and renewed exercise after prior conditioning.

Researchers also observed a dramatic increase in gene activity during retraining.

“The liver went from expressing 18 differentially regulated genes after initial training to more than 6,000 after retraining,” Hernandez-Saavedra said. “That’s not a subtle effect.”

Although the strongest evidence comes from laboratory mice, the study included a six-week human exercise program involving 20 participants that produced encouraging results.

Researchers found that carboxylesterase activity increased after exercise in humans as well. Those increases were greatest among participants with higher cardiorespiratory fitness and a greater history of previous physical activity, mirroring the retraining response observed in mice.

“We’re cautiously optimistic,” Hernandez-Saavedra said. “The human data we present are preliminary … but the pattern is strikingly consistent with what we found in mice.”

The findings could have important implications for metabolic dysfunction-associated steatotic liver disease, or MASLD, formerly known as nonalcoholic fatty liver disease. The condition affects roughly one-third of adults worldwide and is closely linked to obesity, Type 2 diabetes and cardiovascular disease.

Exercise remains one of the most effective treatments for improving liver health, but maintaining consistent physical activity over time remains a challenge for many people.

“If we can establish that a history of exercise, even interrupted, confers durable protection on the liver and amplifies the response to future training, that changes how we think about exercise prescriptions for people at risk of or already living with MASLD,” Hernandez-Saavedra said. “It also opens the door to new therapeutic targets.”

The researchers are now investigating whether those beneficial exercise memories can eventually be activated therapeutically, potentially allowing scientists to mimic some of exercise’s protective effects for patients unable to engage in regular physical activity.

Still, Hernandez-Saavedra cautioned against overinterpreting the results.

“Our study shows that prior exercise history provides a biological advantage when exercise resumes,” he said. “It does not show that stopping exercise is without consequence.” Many of exercise’s measurable benefits diminished during periods of inactivity, he noted, meaning the memory remains dormant until exercise begins again.

Instead, the research offers encouragement for people who have fallen out of an exercise routine.

“Start again, and don’t be discouraged by the gap,” Hernandez-Saavedra said. “The biology suggests that your previous exercise history is not gone; it’s simply dormant.” Even modest activities such as walking, cycling or light resistance training may be enough to reactivate those molecular pathways.

Scientists caution that several important questions remain unanswered before physicians can apply the findings clinically. Researchers still need to determine how long hepatic exercise memory lasts, whether it differs by age or sex, what types and amounts of exercise activate it most effectively and whether specific carboxylesterase proteins can serve as biomarkers of liver health in humans.

Even so, the study challenges one of the most common assumptions surrounding exercise—that periods of inactivity erase previous gains completely.

“People assume that if they stop, they go back to zero,” Hernandez-Saavedra said. “Our research supports a different view: exercise is an investment that accumulates biological capital in your tissues, including your liver, and that capital doesn’t fully disappear when you stop. The body keeps a record.”

While additional human studies are needed to confirm the mechanisms, the research offers a hopeful message to anyone hesitant to restart an exercise program after months—or even years—away: the body may remember more than previously believed.

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