Researchers here report on an interesting discovery: upregulation of a single protein, A2B receptor, adjusts metabolism in mice in the direction of more muscle mass and less fat mass. This treatment can reverse some of the normal trajectory of aging for muscle and fat mass in older animals, turning back muscle loss and fat gain. This is one of a number of similar desirable enhancements to cellular metabolism discovered over the past few decades – see the work on follistatin upregulation, for example. It is typically a long road from this sort of discovery in mice to initial tests in human subjects, particularly given the lack of any existing approved A2B receptor agonist drugs.

On their surface, cells carry numerous different “antennas”, called receptors, which can receive specific signal molecules. These then trigger a specific reaction in the cell. One of these antennas is the A2B receptor. The surfaces of some cells are virtually teeming with it, for example in the so-called brown adipose tissue. Brown adipose tissue, unlike its white-colored counterpart, is not used to store fat. Instead, it burns fat and thereby generates heat.

“We took a closer look at the A2B receptors in brown adipose tissue. In the course of this we discovered an interesting association: The more A2B a mouse produces, the more heat it generates.” Which means the A2B antennas somehow seem to increase the activity of the brown fat cells. But a second observation was even more exciting: Despite their increased fat burning, the animals weigh hardly less than mice with fewer receptors. They are slimmer, but at the same time have more muscles. In fact, the researchers were able to show that the muscle cells of mice also carry the A2B receptor. When this is stimulated by a small molecule agonist, muscle growth in the rodents is increased.

As they age, mice increasingly lose muscle mass – similar to humans. And just like us, they also tend to gain a lot of fat around the hips over the years. However, if they receive the agonist that activates the A2B receptor, these aging effects are inhibited. Their oxygen consumption (an indicator of energy dissiption) increases by almost half; moreover, after four weeks of treatment they have as much muscle mass as a young animal. In order to see whether the results were also meaningful for humans, the researchers examined human cell cultures and tissue samples. They found that in people with a large number of A2B receptors, the brown adipose tissue works at a higher rate. At the same time, their muscle cells consume more energy, which may indicate that they are also more active and may be more likely to be regenerated.