Ask anyone why people are overweight and unfit. The question invariably elicits an eye rolling “like duh” response. These people eat too much and don’t exercise. The explanation is obvious and these lazy gluttonous folks are to blame.

New findings suggest it’s not that simple.

Shedloads of data have documented the beneficial effects of exercise. However a growing body of research has shown that not everyone derives similar benefits from training. This exercise resistance was thought to be determined at or before birth but what mediated the condition was unknown.

Hirofumi Misu’s labratory appears to have decoded the problem. In a remarkable new study published in Nature Medicine they demonstrate that exercise resistance is caused by a liver protein, selenoprotein P (SeP), which binds a receptor in muscle.

Mice with low levels of SeP exposed to treadmill training, even when fed a high-fat diet, exhibited greater endurance capacity than normal mice with similar training. Conversely, mice treated with SeP failed to benefit from the exercise.

That’s an important breakthrough for mice but what about us humans, you say.

The investigators also studied a group of sedentary, postmenopausal women without obesity or diabetes. They underwent an aerobic training program of walking and cycling 3 days per week for 8 weeks.

Increased pre-training levels of SeP predicted a failure to increase endurance capacity with the exercise regimen.

How SeP causes exercise resistance may be the most interesting part of this story.

Reactive oxygen species, a product of metabolic oxidation, have been linked to inflammatory diseases, cancer and aging. The public has been inundated with the benefits of antioxidants (vitamins C and E, berries…). Recent research suggests that antioxidant supplements may be worse than ineffective.

Exercise generates reactive oxygen species. A 2009 study indicated that supplementation with vitamins C and E markedly diminished the positive effects of exercise. We now know that exercise-induced reactive oxygen species trigger molecular adaptations that mediate the benefits of physical activity.

SeP is an antioxidant. It has been shown to contribute to insulin resistance and hyperglycemia in type 2 diabetes. High levels of this protein are too much of a good thing. Like antioxidant supplements, excess SeP sabotages the beneficial effects of exercise.

Some people may be born with high SeP. However recent studies suggest SeP levels increase with age and may contribute to age-related exercise resistance.

This news does much to further our understanding of the most powerful promoter of health, physical activity.

It should not be interpreted as an argument for some to lead a sedentary life. But hopefully it restrains our rush to judgment of those who appear unfit.

Originally published at on April 12, 2017.