A Kobe University research team has uncovered a potential reason why some people struggle to lose weight despite regular exercise. Their study focused on signal molecules that respond to short-term exercise and regulate energy metabolism. Mice lacking these specific molecules burned less fat during workouts and were more prone to weight gain. This discovery, which also appears relevant in humans, could pave the way for new obesity treatments.
For years, the weight loss equation seemed simple: calories in minus calories out. But many people find it harder to shed pounds than others, even with similar diets and exercise routines. Scientists have long known about a protein called PGC-1α that links exercise to its effects on the body. However, its exact role remained unclear due to conflicting experimental results.
OGAWA Wataru, an endocrinologist at Kobe University, explains: “These new PGC-1α versions, called “b” and “c,” have almost the same function as the conventional “a” version, but they are produced in muscles more than tenfold more during exercise, while the a version does not show such an increase.”
Mice Studies Reveal Crucial Differences
To test their theory, the researchers created mice lacking the b and c versions of PGC-1α but retaining the standard a version. They then measured muscle growth, fat burning, and oxygen consumption during rest and various exercise durations.
The results, published in the journal Molecular Metabolism, showed that while all versions of PGC-1α cause similar biological reactions, their production levels significantly impact overall health. Mice lacking the b and c versions essentially couldn’t respond to short-term activity, consuming less oxygen and burning less fat during and after workouts.
Human Implications and Future Treatments
The team also studied human subjects with and without type 2 diabetes. They found that individuals who produced more b and c versions of PGC-1α consumed more oxygen and had lower body fat percentages, regardless of diabetes status.
“Thus, the hypothesis that the genes in skeletal muscle determine susceptibility to obesity was correct,” Ogawa summarizes.
Interestingly, long-term exercise stimulated production of the standard a version of PGC-1α in all mice, leading to increased muscle mass regardless of their ability to produce the alternative versions.
The researchers also discovered that the b and c versions of PGC-1α play a role in maintaining body temperature. Mice unable to produce these versions struggled to tolerate cold conditions, potentially contributing to their higher body fat levels.
Ogawa and his team believe these findings could lead to new obesity treatments: “Recently, anti-obesity drugs that suppress appetite have been developed and are increasingly prescribed in many countries around the world. However, there are no drugs that treat obesity by increasing energy expenditure. If a substance that increases the b and c versions can be found, this could lead to the development of drugs that enhance energy expenditure during exercise or even without exercise. Such drugs could potentially treat obesity independently of dietary restrictions.”
The team is now investigating the mechanisms that increase production of the b and c versions of PGC-1α during exercise. This research, funded by the Japan Society for the Promotion of Science, involved collaboration with several other institutions, including Tokushima University, the Karolinska Institutet, and Kyoto University.
As obesity rates continue to rise globally, this discovery offers a promising new avenue for understanding and potentially treating stubborn weight issues. While further research is needed, the identification of these specific PGC-1α versions could revolutionize our approach to exercise-related weight loss and metabolic health.
