Summary: Researchers identify a neuromuscular circuit that links the burning of muscle fat during physical exercise to the action of a protein in the brain.
An article published in Scientists progress describes a neuromuscular circuit that links the burning of muscle fat to the action of a protein in the brain.
The results, obtained in Brazil by researchers from the State University of Campinas (UNICAMP) and the University of São Paulo (USP), contribute to a better understanding of how regular physical exercise contributes to the weight loss, reinforcing the importance of this habit for good health. .
“We set out to study the action of a protein called interleukin 6 [IL-6], which is a pro-inflammatory cytokine but performs different functions in certain situations, including exercise. In this case, the function is to burn muscle fat,” said Eduardo Ropelle, the paper’s final author. Ropelle is a professor at the School of Applied Sciences (FCA) at UNICAMP in Limeira and is supported by FAPESP.
The Ropelle-led group had previously observed in mice that muscle fat oxidation started immediately in the legs when the protein was injected directly into the brain.
This part of the study was conducted as part of Thayana Micheletti’s master’s research. She carried out part of the analysis during a research internship at the University of Santiago de Compostela in Spain.
The researchers analyzed the results to find out if there was a neural circuit linking the production of IL-6 in the hypothalamus, a region of the brain that controls several functions, to the breakdown of skeletal muscle fat.
This part of the study was conducted with the collaboration of Carlos Katashima, currently in postdoctoral training at the Molecular Biology of Exercise Laboratory (LaBMEx) of FCA-UNICAMP, directed by Ropelle.
Previous studies have shown that a specific part of the hypothalamus (the ventromedial nucleus) can alter muscle metabolism when stimulated. By detecting the presence of IL-6 receptors in this region of the brain, Brazilian researchers formulated the hypothesis that the protein produced there could activate a neuromuscular circuit promoting the burning of fat in skeletal muscles.
Several experiments were performed to demonstrate the existence of the circuit. In one, Katashima and his colleagues excised part of the sciatic nerve in one of each mouse’s legs. The sciatic nerve runs from the bottom of the spine to the feet.
When IL-6 was injected into the brain, fat was burned as expected in the intact legs but not in the leg with the severed nerve.
“Experiment has shown that muscle fat is only metabolized through the nerve connection between the hypothalamus and the muscle,” Katashima said.
To find out how the nervous system was related to the muscles, the researchers administered drugs that blocked the mice’s alpha and beta-adrenergic receptors, in this case responsible for receiving nerve signals for the muscles to perform the function determined by the brain.
Blocking beta-adrenergic receptors had little effect, but muscle fat oxidation either stopped or was greatly reduced when alpha-adrenergic receptors were blocked.
Computer simulations (in silico analysis) showed that the expression of the hypothalamic IL-6 gene was strongly correlated with two muscle subunits of alpha-adrenergic receptors (alpha2A and alpha2C adrenoceptors).
When IL-6 was injected into the brains of mice genetically modified not to produce these receptors, the results were validated: leg muscle fat was not metabolized in these mice.
“An important finding of the study was the association between this neuromuscular circuitry and afterburn, which is the oxidation of fat that occurs after exercise has stopped. This was thought to be secondary, but in In fact, it can last for hours and should be considered vitally important to the weight loss process,” Ropelle said.
“We showed that exercise not only produces IL-6 in skeletal muscle, which was already known, but also increases the amount of IL-6 in the hypothalamus,” Katashima noted.
“It is therefore likely that the effects last much longer than the duration of the exercise itself, highlighting the importance of exercise for any obesity intervention.”
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Image: Image is credited to Eduardo Ropelle/FCA-UNICAMP
Original research: Free access.
“Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism” by Carlos Kiyoshi Katashima et al. Scientists progress
Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism
Hypothalamic interleukin-6 (IL6) exerts broad metabolic control.
Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle.
Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation and mitochondria-related genes in skeletal muscle of isogenic BXD mouse strains and humans.
We have shown that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to alter skeletal muscle fatty acid metabolism.
To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuitry is required to underlie the activation of AMPK/ACC signaling and post-exercise fatty acid oxidation.
Finally, selective downregulation of the IL6 receptor in VMH abolished the effects of exercise to maintain AMPK and ACC phosphorylation and fatty acid oxidation in muscle after exercise.
Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in skeletal muscle.