Communication between muscle and adipose tissue mapped

Breaking new ground 24. okt 2020 4 min Associate Professor Jonas Thue Treebak Written by Kristian Sjøgren

Obtaining beneficial effects from exercise requires that muscles and adipose (fat) tissue communicate. Now, researchers have mapped important aspects of how this communication takes place.

Every one of our cells has a gene that encodes a protein called DICER.

DICER helps to mature microRNAs, which regulate the body’s expression of genes and proteins. DICER is therefore important for cells’ metabolism, and previous studies have shown that DICER plays important roles, especially in fat tissue. For example, DICER abundance in fat tissue declines with age, and mice die prematurely if they lack this protein in their fat tissue.

Conversely, research has also shown that caloric restriction, such as feeding mice slightly less than what they require, can partly counteract the age-related decline in DICER.

Danish researchers have now been involved in discovering that exercise also regulates DICER and that this results from molecular communication between muscles and fat tissue.

The discovery was recently published in the Proceedings of the National Academy of Sciences of the United States of America.

“Exercise requires interaction between many organs and not merely muscles. Muscles need sugar from the liver and fat from the adipose tissue, and organs and tissues must therefore communicate to enable the muscles to cope with the energy stress to which they are exposed during exercise. We have mapped aspects of this communication between the various tissues,“ says Jonas Thue Treebak, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

DICER plays an important role in energy metabolism during exercise

Jonas Thue Treebak and his colleagues from the University of Campinas, São Paulo, Brazil first investigated how mice lacking DICER respond to having to exercise.

They let mice run on treadmills and then took tissue samples and blood samples to measure many biological parameters.

The researchers found that the mice that lacked DICER in the adipose tissue did not adapt to exercise training in the same way as ordinary mice.

When healthy and fit mice – and humans – exercise, the body’s energy expenditure adapts by changing the ratio between the various energy sources it uses.

The body universally adapts by burning more fat and less sugar, because fat is an almost inexhaustible resource in the body, whereas very little sugar is stored.

“Mice lacking DICER did not adapt to the exercise by altering their metabolism towards burning more fat. This confirms that DICER influences the communication between fat tissue and muscle during exercise and that DICER is important for nudging the metabolism towards more fat-burning. Conversely, upregulating DICER affects the processes leading to higher fat burning,“ explains Jonas Thue Treebak.

Enzyme in the muscle directs the communication with adipose tissue

To better understand the communication between the muscles and the adipose tissue, the researchers looked for the factor in the muscles that directs DICER to upregulate when fat needs to be burned.

Specifically, the researchers focused attention on 5-AMP-activated protein kinase (AMPK).

AMPK is already known to play a role during exercise. The enzyme acts as an energy sensor and is activated in the muscle and adipose tissue and in the liver when the cells are exposed to energy stress.

“When mice lack AMPK in skeletal muscle, they do not manage to upregulate DICER in the adipose tissue in connection with training. This was surprising, but it shows that AMPK is important for signalling to fat tissue that it needs to upregulate DICER so that the metabolism can be adjusted. Further, mice lacking AMPK in their adipose tissue did not upregulate DICER in adipose tissue. AMPK in both muscle and fat tissue is therefore crucial for upregulating DICER in connection with exercise,“ says Jonas Thue Treebak.

How exercise affects DICER is most noticeable in younger people

Following their observations in mice, the researchers went a step further and investigated whether they could find similar communication between muscle and fat tissue in humans.

Specifically, they obtained fat biopsies from a group of participants about 35 years old and from a group of participants about 65 years old before and after high-intensity interval training.

This experiment showed that both younger and older people upregulate DICER in adipose tissue in response to exercise, but the younger trial participants had the largest percentage change.

“DICER is upregulated in adipose tissue if you exercise, but the effect seems to be greatest among younger people. However, we do not know yet whether this difference means that older people have more difficulty adjusting to exercise,” explains Jonas Thue Treebak.

Muscle and fat communicate through the blood

In the experiments with mice, the researchers examined how muscles and adipose tissue communicated.

The researchers achieved this intelligently by taking blood from mice that had exercised and injecting it into sedentary mice and then investigating how this affected the concentrations of DICER in the fat tissue.

This experiment showed that something in the blood of the exercised mice caused the levels of DICER to rise – also in the untrained mice.

“This is a very interesting aspect of our research: we can show that communication takes place through the blood through one or more previously unknown signalling molecules. Our results show that muscles during exercise secrete something into the blood that aims to inhibit the fat cells’ use of sugar and that increases the release of fatty acids from fat tissue, which the muscles can then use during exercise,“ says Jonas Thue Treebak.

MicroRNAs make fat cells more active

The researchers also investigated which microRNAs are specifically increased when DICER is upregulated with exercise.

These analyses revealed that more of microRNA 203 is specifically being made.

In addition, the same microRNAs were downregulated with age and also in obese mice.

In experiments with cell cultures, the researchers examined what happens to fat cells when exposed to higher or lower concentrations of microRNA 203.

The results showed that, if microRNA 203 is overexpressed in fat cells, they become more oxidative and more efficiently use the energy contained in them. Conversely, fat cells with downregulated concentrations of microRNA 203 become better at utilizing sugar.

“In this situation, we would rather have high concentrations of microRNA 203 high in our fat tissue because we do not want the adipose tissue and muscles to absorb sugar from the blood but instead use the energy in the fat tissue,” explains Jonas Thue Treebak.

May improve muscle functioning among older people

Jonas Thue Treebak says that the research indicates how muscle and fat communicate to optimize the use of different energy sources during exercise.

“This is one way of adapting when muscles are stressed,” says Jonas Thue Treebak.

The discovery helps us to understand the effect of exercise, and this may be used in the future to develop drugs that can upregulate DICER or microRNA 203 in fat tissue. In theory, we will then be able to produce the effects of exercise without exercising, which may improve muscle function.

“This is very speculative, but it may be one perspective,” says Jonas Thue Treebak.

Jonas Thue Treebak also says that the next step in the effort to understand the communication between fat tissue and muscle cells is to identify the factor in the blood that directs this part of the communication.

“We do not know the molecular targets for microRNA 203, and we also want to identify them,” he says.

Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise” has been published in the Proceedings of the National Academy of Sciences of the United States of America. Several co-authors are employed at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

The research activities of my group are directed towards interrogating the signaling pathways controlling cellular and whole body glucose and lipid ho...

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