Study: Levels of Liver Fat Biomarker Associated with Metabolic Health Benefits of Regular Exercise

While genetics and other factors like age and sex contribute to each individual’s response to exercise, little is known about the biological mechanisms by which physical activity brings about beneficial changes to the body. In a recent study led by cardiologists at Beth Israel Deaconess Medical Center (BIDMC), scientists found that increasing exercise can lower levels of dimethylguanidino valeric acid (DMVG), a molecule in the blood linked to poor health outcomes. However, the researchers were surprised to find that people with higher baseline levels of DMVG – those with “more room to improve” – actually saw less benefit from exercise than people with lower baseline levels of DMVG – those in better health to begin with. The study was recently published in JAMA Cardiology.

Led by corresponding author Robert Gerszten, MD, chief of cardiovascular medicine at BIDMC, the scientists were interested in studying DMGV based on their previous research findings showing that the molecule was a marker of liver fat and that circulating levels were tied the development of type 2 diabetes up to 12 years prior to disease onset.

"In our earlier work, what we found particularly compelling was the fact that patients who underwent weight loss surgery had decreases in DMGV,” Gerszten explained, MD. “In this new study, we were curious to see if exercise could also modulate levels of DMGV."

Gerszten’s team measured blood levels of DMGV in nearly 440 otherwise healthy participants from the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study – a 20-week, single-arm endurance exercise clinical trial performed in multiple centers between 1993 and 1997 – before and after a chronic exercise training program. As part of the HERTIAGE Family Study, these patients underwent comprehensive cardiopulmonary exercise testing (CPET), body measurements, lipid profiling, and insulin and glucose testing both before and after the exercise intervention in order to study the effects of chronic exercise on these parameters. Expanding on the HERITAGE Family Study’s scope, the researchers added metabolite profiling to help identify predictors of exercise responsiveness, and to better inform the researchers’ understanding of the biologic pathways involved in exercise adaptation.

This new study had three principal findings. First, the researchers found that DMGV was associated with adverse metabolic risk even in very young individuals free of overt disease. Second, they found regular exercise modulated circulating levels of DMGV and that these changes correlated with the changes in associated clinical traits after exercise training. Lastly, Gerszten and colleagues showed that higher baseline levels of DMGV were associated with reduced improvements in lipid traits and insulin sensitivity after exercise training.

“Our findings indicate that DMGV levels may identify individuals who are less responsive to the metabolic health benefits of endurance exercise training and may require additional therapies beyond guideline-directed exercise to improve their metabolic health,” said Gerszten. “These results highlight the potential application of metabolomics to inform targeted exercise therapy.”

The findings will help Gerszten and colleagues characterize the biologic mechanisms that underlie exercise-mediated health benefits so that they can be harnessed into new therapeutic strategies. Another major goal of this research was to use molecular phenotyping tools, like metabolomics, to tailor exercise therapies to individuals or to a given disease state.

In addition to Gerszten, co-authors include Jeremy M. Robbins, MD, Daniel E. Cruz, MD, Matthew Herzig, BA, and Jordan Morningstar, BA, of BIDMC; Mark A. Sarzynski, PhD, of University of South Carolina, Columbia; Thomas J. Wang, MD, of Vanderbilt University, Yan Gao, MPH, and James G. Wilson, MD, PhD, of University of Mississippi Medical Center; and Claude Bouchard, PhD, and Tuomo Rankinen, PhD, of Pennington Biomedical Research Center.

This study is supported by the John S. LaDue Memorial Fellowship in Cardiology at Harvard Medical School, the National Institute of General Medical Sciences (grant U54 GM104940; Centers of Biomedical Research Excellence Center grant 8P20 GM-1033528, and grant U54GM115428 ), and the National Institutes of Health (grants R01DK081572; U24DK112340 ).

Gerszten reported grants from the National Institutes of Health during the conduct of the study. Wang reported grants from the National Institutes of Health during the conduct of the study. Wilson reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Rankinen reported grants from National Heart, Lung, and Blood Institute during the conduct of the study. No other disclosures were reported.