Weight training reprograms liver cells and helps reverse obesity-related damage

A study by the State University of Campinas using mice reveals that strength training modulates the liver’s genome, restoring insulin sensitivity and combating fat accumulation in the organ.

By Maria Fernanda Ziegler  |  Agência FAPESP – A study conducted at the State University of Campinas (UNICAMP) in the state of São Paulo, Brazil, shows that the benefits of weight training extend beyond muscle growth and weight loss. In experiments with mice, the researchers observed that strength training induces true molecular reprogramming in the liver. This discovery helps us understand how such training modulates genome function to mitigate non-alcoholic fatty liver disease, a condition characterized by fat accumulation in the liver that is closely linked to the onset of type 2 diabetes.

“We wanted to understand how something that occurs in the muscles could influence and benefit a problem in the liver. To do so, we investigated the core of metabolism, which is our DNA. The goal was to understand how obesity damages that DNA and how weight training can protect it,” explains Leandro Pereira de Moura, a professor at the School of Applied Sciences (FCA-UNICAMP) and the research coordinator, in an interview with Agência FAPESP.

The study, which was supported by FAPESP, was published in November in the journal Life Sciences.

To discover how muscle activity affects the liver, the research focused on epigenetics. Epigenetics is the study of how external factors, such as lifestyle habits and environmental conditions, alter gene function without changing the DNA code.

One of the most studied epigenetic phenomena is DNA methylation. It involves adding a chemical molecule, the methyl group, to the promoter region of a gene, which acts as the “on switch.” This chemical mark functions as a physical barrier that makes the gene less accessible to the cell’s enzymes, thereby inhibiting its activity.

In experiments with rodents, researchers found that eight weeks of weight training was sufficient to alter the methylation of the MTCH2 gene (mitochondrial transporter homolog 2), which plays a significant role in how the liver processes and utilizes energy.

As Moura explains, obesity forces the liver to function in a toxic environment. Excess fat accumulates in hepatocytes, the liver’s main cells, triggering chronic inflammation and mitochondrial dysfunction. Mitochondria are the cell’s “powerhouses.” The liver attempts to regenerate itself, but without sufficient energy, this process fails. Healthy tissue is gradually replaced by scar tissue (fibrosis), which slowly destroys the organ’s function. In this scenario of extreme stress, the body dysregulates the function of the MTCH2 gene, which accelerates the progression of the disease.

In experiments with trained mice, the scientists observed something intriguing: although liver cells sent the genetic command (messenger RNA) to activate MTCH2, the amount of the linked protein decreased. According to Moura, this occurs because weight training restored the organ’s energy capacity and reduced inflammation. Upon realizing that the environment was no longer toxic, the body switched off “emergency mode.” Without cellular stress and signals of self-destruction, the body blocked the final stages of forming this protein.

Insulin resistance

The liver plays a key role in maintaining stable blood sugar levels (glycemia), which is essential for the proper functioning of all organs, especially the brain. The liver stores excess sugar in the form of glycogen shortly after meals under the control of insulin. During periods of fasting, the liver releases this reserve back into the bloodstream. Under normal conditions, insulin signals the liver to stop releasing glucose when the body has enough fuel. However, when the liver is inflamed and filled with fat, it becomes insulin resistant, meaning it ignores this signal and continues to release sugar into the bloodstream. The study found that the livers of obese rodents that underwent strength training regained their sensitivity to insulin.

The results also indicate that physical activity inhibits the action of enzymes that cause fibrosis and uncontrolled cell growth. Physical activity also boosted the production of ATP5, a protein essential for mitochondrial energy generation. “With abundant energy, the cells exit their state of alert and stop activating the MTCH2 gene, promoting tissue regeneration,” Moura summarizes. “Lifting weights not only strengthens muscles, but also regulates how liver DNA functions.”

The article “Epigenetically modulated MTCH2 and regulated ATP5 in the liver of obese mice subjected to strength training” can be read at sciencedirect.com/science/article/abs/pii/S0024320525007416.