Study helps to understand how physical exercise induces fat burning in muscles

A study published in the journal Science Advances described, for the first time, a neuromuscular circuit that links the burning of fat in the muscle to the action of a protein in the brain.

The results, obtained by researchers from the State University of Campinas (Unicamp) and the University of São Paulo (USP), help to understand how the practice of physical exercise helps in weight loss and reinforce the importance of this habit for health.

“The work aimed to study the action of a protein called interleukin 6 [IL-6], which has an inflammatory characteristic, but which in some situations, such as physical exercise, assumes different functions. In this case, the burning of fat in the muscle”, explains Eduardo Ropelle, professor at the Faculty of Applied Sciences (FCA) at Unicamp, in Limeira, who coordinated the study supported by Fapesp.

The group led by the researcher had already observed that mice that had the protein injected directly into the brain immediately started a process of fat oxidation in the paw muscle. This part of the study was carried out during the master’s degree of Thayana Micheletti, a Fapesp scholarship holder.

Micheletti carried out part of the analysis during an internship at the University of Santiago de Compostela, in Spain.

With the results, the researchers sought to understand if there was a circuit that linked the production of IL-6 in the hypothalamus, part of the brain that controls various functions, with the breakdown of fat observed in musculoskeletal tissue.

This stage of the research had the collaboration of Carlos Katashima, who is currently doing a postdoctoral internship at the Laboratory of Molecular Biology of Exercise (LaBMEx) at FCA-Unicamp, coordinated by Ropelle.

Previous studies indicated that a specific part of the hypothalamus, the ventromedial portion, could alter muscle metabolism when stimulated. Upon detecting the presence of the IL-6 receptor in that part of the brain, Brazilian researchers arrived at the hypothesis that the action of the protein produced there could trigger a neuromuscular circuit, favoring the burning of fat in the musculoskeletal tissue.

To demonstrate the existence of the circuit, several experiments were performed. In one, Katashima and colleagues cut the sciatic nerve, which connects the spine to the thigh muscle, in just one of the mice’s paws.

When IL-6 was injected into the brain, fat burning occurred as expected in the intact paw, but not in the one that had the nerve cut. “The experiment showed, therefore, that the burning of muscle fat only occurs thanks to the nervous connection between the hypothalamus and the muscle”, says Katashima.

blocked receivers

It remained for researchers to discover how this connection between the nervous and muscular systems was made. For this, they administered to the mice drugs that block the so-called alpha and beta adrenergic receptors, in this case responsible for receiving the nerve signal so that the muscle can perform the function determined by the brain.

While blocking beta receptors was not as effective, “turning off” alpha adrenergic receptors caused fat oxidation in muscle to be greatly reduced or not at all.

Computational analyzes (in silico) showed a strong correlation between the IL-6 gene in the hypothalamus and two subunits of alpha receptors in muscle, alpha2A and alpha2C. The results were validated when the researchers injected IL-6 into the brains of mice that do not produce these specific receptors and the animals did not show muscle fat breakdown.

“An important finding of this study was that it associated this neuromuscular circuit with the so-called ‘afterburn’, which is the burning of fat that happens after we stop exercising. This was once considered secondary, but in fact it can last for hours and should be considered of fundamental importance in the weight loss process”, points out Ropelle.

“We showed that physical exercise, in addition to producing IL-6 in the muscle, as was already known, also increases the content of this protein in the hypothalamus. Therefore, the effects are probably much longer lasting than just during the activity itself. This shows once again the importance of physical exercise in an intervention against obesity”, concludes Katashima.

The work was also supported by Fapesp through a Thematic Project, coordinated by Adelino Sanchez Ramos da Silva.

The article “Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism” can be read here.