Adipose tissue is not just a simple reservoir of energy in times of food shortages. It contributes significantly to the regulation of metabolism and releases various molecules into the bloodstream, including microRNAs that modulate the expression of key genes in various parts of the organism, including the liver, pancreas, and muscles.
Research has shown that aging and obesity can both interfere with the production of these regulatory microRNAs by adipose tissue and promote the development of diseases such as diabetes and dyslipidemia.
The good news is that this degenerative process can be reversed with regular aerobic exercise, according to a study published in Procedure of the National Academy of Sciences (PNAS).
"Experiments with mice and humans have shown that aerobic exercise stimulates the expression of an enzyme called DICER, which is essential for processing these microRNAs. We therefore observed an increase in the production of these regulatory molecules by fat cells with several metabolic benefits. “
Marcelo Mori, professor at the Institute of Biology at the University of Campinas
Mori is a key researcher for the project, supported by FAPESP (São Paulo Research Foundation) and carried out in partnership with groups at the University of Copenhagen in Denmark and Harvard University in the USA.
The experiments were carried out during postdoctoral research by Bruna Brasil Brandão, Mori?
7;s former PhD student and now at Harvard Medical School as a research assistant in Professor C. Ronald Kahn’s laboratory.
The results showed the occurrence of communication between muscle and fat tissue during aerobic exercise via signaling molecules that are secreted into the bloodstream. This exchange of information makes the energy consumption of fat cells more efficient, allows the metabolism to adapt to exercise and improve muscle performance.
The mice were subjected to a 60 minute treadmill running protocol for eight weeks. As they got fitter, the speed and incline of the treadmill increased.
In the end, in addition to improving performance, the scientists found a significant increase in adipocyte levels of DICER expression, which was accompanied by a decrease in body weight and visceral fat.
When they repeated the experiment with mice that were genetically engineered so as not to express DICER in fat cells, the researchers found that the beneficial effects of aerobic exercise were far less. “The animals did not lose weight or visceral fat, and their general fitness did not improve,” said Mori. “We also observed that fat cells used the energy substrate in these genetically modified mice differently than they did in wild mice, so that less glucose was available for the muscles.”
In humans, six weeks of high-intensity interval training (HIIT) was enough to increase the amount of DICER in adipose tissue by an average of five times. The effect was seen in both younger volunteers around 36 years of age and older volunteers around 63 years of age. The response varied considerably between individuals, with DICER increasing up to 25-fold in some and very little in others.
The role of DICER and microRNA processing in adipose tissue was first described in an article in 2012 Cell metabolism reports on a study carried out by Mori and Khan in collaboration with an international group of researchers.
The most important result was that the expression of DICER in the adipose tissue of mice decreased with increasing weight gain of the animals and this shortened their lifespan. The study also showed that calorie restriction can reverse the harmful effects of obesity.
In another study published in the journal in 2016 aging Mori and his group showed that calorie restriction in mice prevented the age-related decline in microRNA production by adipose tissue and the development of type 2 diabetes. In a 2017 study in nature They demonstrated that the microRNAs produced by adipose tissue entered the bloodstream and acted on distant tissues and regulated gene expression.
“In this latest study, we found that aerobic exercise like cutting calories, thanks to the activation of a very important metabolic sensor, the AMPK enzyme, can reverse the decline in DICER expression and microRNA production [adenosine monophosphate-activated protein kinase]”Said Mori.
The sensor is activated, he explained, when the cell uses ATP (adenosine triphosphate, the molecule that acts as an energy substrate for cells) and creates an energy deficit. In experiments with mice, the researchers found that aerobic exercise activated AMPK in muscle cells and that this somehow induced DICER expression in fat cells.
“The obvious conclusion is that the effect on gene expression occurs in the same cell where the energy deficit occurs, which is the case, but here the sensor is also activated in the muscles and controls the response that occurs in the adipose tissue,” said he said.
To confirm communication between tissues, the scientists collected blood serum from a trained animal and injected it into a sedentary animal. This “treatment” increased DICER expression in adipose tissue. In another experiment, they incubated cultured adipocytes with serum from trained mice and observed the same effect.
“This finding suggests that trained individuals have one or more molecules in their bloodstream that directly induce metabolic improvement in adipose tissue,” said Mori. “If we can identify these molecules, we can investigate whether they also produce other benefits of aerobic exercise such as cardioprotection. In addition, we could consider turning this knowledge into a drug at some point.”
In order to gain an even more detailed understanding of the metabolic regulation mechanism, the researchers analyzed all thousands of microRNAs expressed in the organism of the trained mice and compared them with those in sedentary mice.
“We have identified a molecule called miR-203-3p, the expression of which increases with both exercise and calorie restriction,” said Mori. “We have shown that this microRNA is responsible for promoting metabolic adaptation in adipocytes. When muscles use up all of their glycogen during prolonged training, molecular signals are sent to the adipose tissue and miR-203-3p optimizes fat metabolism. We found this metabolism flexibility which is essential for good health and improved performance. “
Without this modulation, the adipocytes’ glucose consumption increases during exercise, leaving the muscles with less energy substrate, he added. This can lead to hypoglycemia, one of the major performance impairments for athletes.
“In genetically engineered mice that do not express DICER in adipocytes, this conversation between adipose tissue and muscles does not take place. It is a model that mimics aging and obesity. When DICER decreases, metabolic health is poor and degenerative processes accelerate”, said Mori.
São Paulo Research Foundation
Brandão, BB, et al. (2020) Dynamic changes in DICER levels in adipose tissue control the metabolic adaptations to exercise. Procedure of the National Academy of Sciences. doi.org/10.1073/pnas.2011243117.