Protein Discovery Will Revolutionize Obesity Treatment

The discovery by Kobe University of new variants of the PGC-1⍺ protein, which are more active during exercise and may regulate fat burning and energy metabolism, suggests a potential breakthrough in treating obesity by increasing energy expenditure rather than simply reducing caloric intake.

New findings highlight the “b” and “c” variants of PGC-1⍺ as critical for enhancing fat burning and energy metabolism during exercise, offering new avenues for the treatment of obesity.

Some people lose weight more slowly than others after a workout. A research team from Kobe University has found an explanation for this phenomenon. They studied what happens to mice that cannot produce signaling molecules that specifically respond to short-term exercise and regulate the body’s energy metabolism. These mice consume less oxygen during workouts, burn less fat, and are therefore more likely to gain weight. Since the team also discovered this link in humans, the new knowledge gained about this mechanism could pave the way for treating obesity.

The Link Between Exercise and Fat Burning

It is well known that exercise causes fat burning. But for some people, it is much more difficult than for others, which leaves doubt as to whether the mechanism of weight loss or gain is as simple as “calories in minus calories out.” Researchers have already identified a signaling molecule, a protein called “PGC-1⍺,” that appears to link exercise to its effects. However, it has not been possible to determine whether increased amounts of this protein actually cause these effects, as some experiments have suggested it, while others have not.

More recently, Kobe University endocrinologist Wataru Ogawa and other researchers have discovered that there are actually several different versions of this protein. Ogawa explains: “These new versions of PGC-1α, called ‘b’ and ‘c’, have almost the same function as the classic ‘a’ version, but they are produced in muscles more than ten times more during exercise, while the a version does not show such an increase.” So his team set out to prove the idea that it is the newly discovered versions, and not the already known one, that regulate energy metabolism during exercise.

Different versions of the PGC-1⍺ signaling molecule respond to different stimuli. The standard version (“a”) is produced in response to long-term exercise, while alternative versions (“b/c”) are produced in response to short-term exercise or exposure to cold. The absence of these versions makes it harder for affected individuals to respond to these stimuli by burning fat or building muscle mass. Credit: K. Nomura et al. Published by Elsevier GmbH. DOI: 10.1016/j.molmet.2024.101968

To do this, the researchers created mice that lacked the b and c versions of the PGC-1⍺ signaling molecule while retaining the standard a version, and measured the mice’s muscle growth, fat burning, and oxygen consumption at rest and during short- and long-term exercise. They also recruited human subjects with and without type 2 diabetes and subjected them to tests similar to those of the mice, since insulin– it is known that intolerant and obese people have reduced levels of the signaling molecule.

Biological consequences of protein variants

Ogawa and his team published their results in the journal Molecular metabolism. They found that while all versions of the signaling molecule cause similar biological responses, their different levels of production have profound consequences for the body’s health. The absence of the alternative versions b and c of PGC-1⍺ means that the body is essentially blind to short-term activity and does not adapt to these stimuli, causing these individuals to consume less oxygen and burn less fat during and after workouts.

In humans, the research team found that the more the test subjects produced versions b and c of the signal molecule, the more oxygen they consumed and the less body fat they had, in both healthy individuals and those with type 2 diabetes. “So the hypothesis that skeletal muscle genes determine susceptibility to obesity was correct,” Ogawa said of the findings.

However, they also found that long-term exercise stimulates production of the standard version of PGC-1⍺, and that mice that exercised regularly for six weeks showed increases in muscle mass, whether or not they could produce the alternative versions of the signal molecule.

Wataru Ogawa, an endocrinologist at Kobe University, has elucidated the physiological role of different versions of a signaling molecule that links exercise to its effects. He found that mice lacking a new version of the signaling molecule produced specifically in response to short-term exercise burned less fat than mice with both versions. Credit: Wataru Ogawa

Long-term effects and cold tolerance

In addition to production in muscle, the Kobe University team studied how production of different versions of PGC-1⍺ changes in fat tissue and found no relevant effects in response to exercise. However, since animals also burn fat to maintain their body temperature, the researchers also studied the mice’s ability to tolerate cold.

Indeed, they found that production of the b and c versions of the signal molecule in brown adipose tissue increased when animals were exposed to cold, and that the body temperature of individuals that could not 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 could be responsible for metabolic adaptations to short-term stimuli more generally.

Potential treatments for obesity

Ogawa and his team point out that understanding the physiological activity of the different versions of PGC-1⍺ could help design therapeutic 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 versions b and c is found, this could lead to the development of drugs that increase energy expenditure during exercise or even without exercise. Such drugs could potentially treat obesity independently of dietary restrictions.”

The team is currently researching to learn more about the mechanisms that lead to increased production of the b and c versions of the signaling molecule during exercise.

Reference: “Adaptive gene expression of alternative splice variants of PGC-1α regulates whole-body energy metabolism” by Kazuhiro Nomura, Shinichi Kinoshita, Nao Mizusaki, Yoko Senga, Tsutomu Sasaki, Tadahiro Kitamura, Hiroshi Sakaue, Aki Emi, Tetsuya Hosooka, Masahiro Matsuo, Hitoshi Okamura, Taku Amo, Alexander M. Wolf, Naomi Kamimura, Shigeo Ohta, Tomoo Itoh, Yoshitake Hayashi, Hiroshi Kiyonari, Anna Krook, Juleen R. Zierath and Wataru Ogawa, June 15, 2024, Molecular metabolism.
DOI: 10.1016/j.molmet.2024.101968

This research was supported by the Japan Society for the Promotion of Science (Grants 26461337, 16H01391, and 15H04848). It was conducted in collaboration with researchers from the University of Tokushima, Karolinska Institutet, Kyoto University, Gunma University, the National Defense Academy, the Nippon Medical School, the RIKEN Center for Biosystems Dynamics Research, and the Asahi Life Foundation.