Summary: The researchers identify a neuromuscular circuit that links the burning of muscle fat during physical exercise with the action of a protein in the brain.
Font: FAPESP
An article published in Progress of science describes a neuromuscular circuit that links the burning of muscle fat with the action of a protein in the brain.
The findings, obtained in Brazil by researchers from the State University of Campinas (UNICAMP) and the University of São Paulo (USP), contribute to a deeper understanding of how regular physical exercise helps with 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 some situations, including exercise. In this case, the function is to burn muscle fat”, said Eduardo Ropelle, last author of the article. Ropelle is a professor at the Faculty of Applied Sciences (FCA) at UNICAMP in Limeira and is supported by FAPESP.
The group led by Ropelle had already observed in mice that the oxidation of muscle fat began immediately in the legs when the protein was injected directly into the brain.
This part of the study was conducted during Thayana Micheletti’s master’s research. She performed 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 that linked the production of IL-6 in the hypothalamus, a region of the brain that controls several functions, with the breakdown of skeletal muscle fat.
This part of the study was carried out with the collaboration of Carlos Katashima, who is currently doing a postdoctoral internship at the FCA-UNICAMP Laboratory of Molecular Biology of Exercise (LaBMEx), directed by Ropelle.
Previous studies have shown that a specific part of the hypothalamus (the ventromedial nucleus) could alter muscle metabolism when stimulated. By detecting the presence of IL-6 receptors in that region of the brain, Brazilian researchers hypothesized that the protein produced there could activate a neuromuscular circuit that favors the burning of fat from skeletal muscle.
Several experiments were performed to prove the existence of the circuit. In one, Katashima and his colleagues removed part of the sciatic nerve in one leg of each mouse. The sciatic nerve runs from the lower spine to the feet.
When IL-6 was injected into the brain, fat burned as expected in the intact legs, but not in the leg with the severed nerve.
“The experiment showed that muscle fat is metabolized only thanks to the nerve connection between the hypothalamus and the muscle,” Katashima said.
Blocked Receivers
To find out how the nervous system was linked to the muscles, the researchers administered drugs that blocked the alpha and beta adrenergic receptors of the mice, in this case those responsible for receiving nerve signals for the muscles to perform the function determined by the brain.
Blockade of beta-adrenergic receptors had little effect, but muscle fat oxidation stopped or was dramatically reduced when alpha-adrenergic receptors were blocked.
Computer simulations (in silico analyses) showed that hypothalamic IL-6 gene expression was strongly correlated with two muscle alpha-adrenergic receptor subunits (alpha2A and alpha2C adrenoceptors).
When IL-6 was injected into the brains of mice genetically engineered not to produce these receptors, the results were validated: fat from leg muscles was not metabolized in these mice.
“An important finding of the study was the association between this neuromuscular circuit and afterburn, which is the oxidation of fat that occurs after exercise has ceased. This has been considered secondary, but in fact, it can last for hours and should be considered vital to the weight loss process,” said Ropelle.
“We showed that physical 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 said.
“Thus, the effects are likely to last much longer than the duration of exercise itself, underscoring the importance of exercise for any obesity intervention.”
About this exercise and neuroscience research news
Author: press office
Font: FAPESP
Contact: Press Office – FAPESP
Image: The image is credited to Eduardo Ropelle/FCA-UNICAMP
See also
original research: Open access.
“Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism” by Carlos Kiyoshi Katashima et al. Progress of science
Summary
Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism
Hypothalamic interleukin-6 (IL6) exerts extensive metabolic control.
Here, we show that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle.
Bioinformatic analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely related to fatty acid oxidation and mitochondria-related genes in skeletal muscle of isogenic strains of BXD mice and humans.
We show that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify skeletal muscle fatty acid metabolism.
To address the physiological relevance of these findings, we show that this neuromuscular circuitry is required to support activation of AMPK/ACC signaling and fatty acid oxidation after exercise.
Finally, selective downregulation of the IL6 receptor in VMH abolished the effects of exercise in maintaining 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.
