Obesity Treatment Same Workout, Different Weight Loss: Signal Molecule Versions are Key

Some people lose weight slower after workouts, and a Kobe University research team discovered why. Studying mice lacking specific signal molecules that respond to short-term exercise, they found these mice consume less oxygen, burn less fat, and are more prone to weight gain. This connection, also found in humans, could lead to new obesity treatments.

It is well known that exercise leads to the burning of fat. But for some people, this is much more difficult than for others, casting doubt on whether the mechanism behind losing or gaining weight is as simple as “calories in minus calories out.” Researchers have previously identified a signal molecule, a protein by the name of “PGC-1⍺,” that seems to link exercise and its effects. However, whether an increased amount of this protein actually leads to these effects or not has been inconclusive, since some experiments suggested it while others didn’t. More recently, the Kobe University endocrinologist Ogawa Wataru as well as other researchers found that there are actually a few different versions of this protein. Ogawa 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.” His team therefore set out to prove the idea that it is the newly discovered versions, and not the previously known one, that regulate the energy metabolism during workouts.

To do so, the researchers created mice that lack the b and c versions of the signal molecule PGC-1⍺ while they still have the standard a version, and measured the mice’s muscle growth, fat burning and oxygen consumption during rest and short-term as well as long-term workout. They also recruited human test subjects with and without type 2 diabetes and submitted them to similar tests as the mice, because insulin-intolerant and obese people are known to have reduced levels of the signal molecule.

Ogawa and his team published their results in the journal Molecular Metabolism. They found that, while all versions of the signal molecule cause similar biological reactions, their different levels of production have far-reaching consequences for the organism’s health. The lack of the alternative b and c versions of PGC-1⍺ means that the organism is essentially blind to short-term activity and does not adapt to these stimuli, with the effect that such individuals consume less oxygen and burn less fat during and after workouts. In humans, the research team found that the more the test subjects produced the b and c versions of the signal molecule, the more they consumed oxygen and the less percent body fat they had, across healthy individuals and those with type 2 diabetes. “Thus, the hypothesis that the genes in skeletal muscle determine susceptibility to obesity was correct,” summarizes Ogawa these findings. However, they also found that long-term exercise stimulates the production of the standard a version of PGC-1⍺, and mice that exercised regularly over the course of six weeks exhibited an increase in muscle mass irrespective of whether they could produce the alternative versions of the signal molecule or not.

In addition to the production in muscles, the Kobe University team looked at how the production of the different versions of PGC-1⍺ changes in fat tissues, and found no relevant effect in response to exercise. However, since animals also burn fat to maintain body temperature, the researchers also investigated the mice’s ability to tolerate cold. And indeed, they found that the production of the b and c versions of the signal molecule in brown adipose tissue is increased when the animals are exposed to cold, and that the body temperature of individuals that cannot produce these versions dropped significantly under these conditions. On the one hand, this may contribute to these individuals’ having more body fat, but on the other hand it seems to imply that the b and c versions of the signal molecule may be responsible for metabolic adaptations to short-term stimuli more generally.

Ogawa and his team point out that understanding the physiological activity of the different versions of PGC-1⍺ might allow to devise treatment approaches for obesity: “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 are now conducting research to find out more about the mechanisms that lead to the increased production of the signal molecule’s b and c versions during exercise.

Original Article: Adaptive gene expression of alternative splicing variants of PGC-1⍺ regulates whole-body energy metabolism; Molecular Metabolism; DOI:10.1016/j.molmet.2024.101968

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