Longevity Briefs: Is This The ‘Exercise Molecule’ We’ve Been Waiting For?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important:

Exercise is an essential way to keep your body healthy and extend your lifespan. Aside from improving strength and fitness, exercise has a wide range of benefits for the function of organs throughout the body, and protects against most diseases of ageing. Scientists are trying to understand the molecular underpinnings of these benefits in the hope that they can be replicated therapeutically, to treat obesity and diabetes for example.

Scientists have identified many molecules released in response to exercise, but none have so far yielded a satisfactory exercise-mimicking drug. Researchers are always in search of new genes and signalling molecules that could be leveraged to treat or prevent disease.

What did the researchers do:

In this study, researchers looked for molecules in the blood of mice that increased following treadmill running, and also compared molecules in the blood of racehorses taken before and and after a race. The researchers found that the levels of one metabolite, Lac-Phe, were greatly increased in both species, and this was consistent with a previous report in humans. Lac-Phe is made from lactate (a by-product of exercise) and phenylalanine (an essential amino acid).
Next, the researchers took lean mice and obese mice that had been fed a high-fat diet, and gave them regular injections of Lac-Phe, lactate, or phenylalanine over the course of 10 days to see if any of the weight loss effects of exercise could be reproduced.

Key takeaway(s) from this research:

• Lac-Phe injection (but neither of the other treatments) was associated with a decrease in body weight in obese mice. This was found to be due to a decrease in fat tissue.
• Appetite was reduced for 12 hours after injection in the obese mice.
• Lac-Phe did not significantly affect the lean mice.
• Lac-Phe was produced by an enzyme called carnosine dipeptidase 2 (CNDP2), consistent with the findings of previous studies.

They then looked at how mice lacking CNDP2 responded to exercise while being fed a high fat diet. They found that normal exercising animals did not gain weight despite their high fat diet. In contrast, mice lacking CNDP2 did gain weight. This was mainly due to them eating more to compensate for their increased energy expenditure.

So, it seems that Lac-Phe can suppress appetite and induce weight loss specifically in mice that are overweight. Many questions remain, such as whether additional Lac-Phe improves the existing weight-loss effects of exercise. The big question is of course whether this works in humans. It may also be helpful to understand where within the body this molecule is being manufactured. Interestingly, this study found that expression of CNDP2 was particularly high in immune cells, so there is another potential mechanism for the apparent link between exercise, obesity and the immune system.