ABOVE: Some of the health benefits of exercise appear to be mediated through the liver. ©ISTOCK.COM, MARY SWIFT

Plenty of scientific evidence indicates that exercise is good for our health. It benefits our hearts, bones, and muscles, boosts brain health, and may even fight off cancer.1,2,3 Now, a study shows that alongside the muscles and heart, the liver contributes to some of the positive effects of exercise. 

See also “How Exercise Helps Mice Fight Pancreatic Cancer”

Researchers at Stanford University found that after consistent exercise, the liver produces an enzyme that boosts exercise performance, enhances weight loss, and improves glucose tolerance in mice. Published in Cell Metabolism, the study challenges the conventional muscle-centric view of exercise, revealing that tissues throughout the body respond to breaking a sweat.4

See also “Mice With a Healthy Gut Microbiome Are More Motivated to Exercise” 

Jonathan Long, an exercise physiologist and coauthor of the study, said that the reasons why exercise improves health are largely mysterious. “It’s one of the best things you can do for yourself. And despite that, we don’t really know why it’s good for you or how it works.” 

In previous studies, Long learned that certain exercise metabolites in the blood boost weight loss and endurance.5 The team was only able to look at one or two molecules at a time then, but Long was interested in investigating proteins and tissues throughout the body.

For this new study, Long and his team developed proteomics tools to study the mouse secretome: the profile of proteins that cells throughout the body release into the blood in response to exercise. 

The authors used a technique called TurboID, which identifies protein secretion in different Cre-labeled cells within blood plasma. “This allows us to look at the secreted proteins coming out of a certain cell type,” Long explained.

The team profiled protein secretion in 21 different cell types across 10 different tissues in mice and compared the secretomes of mice that had exercised on the treadmill for 60 minutes a day for a week to those of sedentary mice. To their surprise, almost all tissues in the body started either boosting or reducing protein production. 

A particularly striking finding, said Long, was that in response to exercise, liver cells secreted a family of molecules called carboxylesterase 2 (CES2), which were previously thought to be intracellular proteins. Other studies had revealed that boosting CES2 production inside the liver can increase metabolism in mice.6 However, the team showed that CES2 is also released into the body in response to exercise, and it may influence a number of other organ systems. 

To further understand the role of CES2, the researchers genetically engineered mice to overexpress CES2 in their livers and found that the protein improved overall metabolic health. Mice lost weight and had greater endurance and better glucose tolerance than non-genetically engineered mice. The CES2-overexpressing mice could also run faster and for a longer time than their non-genetically engineered counterparts. 

The researchers next genetically engineered a type of CES2 that mice couldn’t keep inside their livers. Mice that expressed this modified CES2 on top of their regular CES2 still experienced increased benefits from exercise compared to normal mice. 

Lisa Chow, an endocrinologist at the University of Minnesota who was not involved in the study, said that the findings were exciting. “When we think about exercise, we always think about the muscle and the heart or the blood vessels. But that's not the case here,” she said. 

However, Chow said that it’s unclear whether exercise, weight loss, or body composition drove the observed changes in protein secretion. In addition, the study was primarily conducted on male mice. “We need to look at female mice and across species, including humans,” Chow said, also noting that considering how the context of exercise, such as time of day, might affect proteins. 

Long said that how CES2 improves endurance or causes weight loss is unclear, but he hopes to dig into this question in the future.

References

  1. Vina J, et al Exercise acts as a drug; the pharmacological benefits of exercise: Exercise acts as a drug. British Journal of Pharmacology. 2012;167(1):1-12. doi:10.1111/j.1476-5381.2012.01970.
  2. Voss MW, et al. Exercise, brain, and cognition across the life span. Journal of Applied Physiology. 2011;111(5):1505-1513. 
  3. Miller TD, et al. Exercise and its role in the prevention and rehabilitation of cardiovascular disease. ann behav med. 1997;19(3):220-229. 
  4. Wei, Wei, et al. “Organism-Wide, Cell-Type-Specific Secretome Mapping of Exercise Training in Mice.” Cell Metabolism, vol. 35, 2023, pp. 1–19., 
  5. Li VL, et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature. 2022;606(7915):785-790. 
  6. Xiao D, et al. Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs. Biochemical Pharmacology. 2013;85(3):439-447.