30 October 2024
The immune system has always been basically seen as a defense against infection. What experts are now beginning to realise is that it is also essential for regulating our fat metabolism. A new study is beginning to unravel how this regulation works.
In order for our bodies to efficiently transform into fat the excess carbohydrates we eat, in a process of “lipogenesis”, two things must happen. First, the immune system's gamma-delta T cells, a type of lymphocytes that are present in large quantities in adipose tissue (a.k.a. fat), have to produce a substance that triggers lipogenesis, called IL-17.
Secondly, there must be a very fine temporal regulation of this production, governed by the internal molecular “clocks” of these immune cells, in order for the production of IL-17 to coincide with the periods of greatest abundance of carbohydrates to be processed.
These are the conclusions of a study published today (October 30th) in the journal Nature, by an international team including two scientists from the Champalimaud Foundation.
“What this work shows is that a large part of our metabolism is regulated by cells of the immune system”, says Henrique Veiga-Fernandes, principal investigator at the Champalimaud Foundation's Immunophysiology Laboratory – and one of the senior co-authors of the new study.
"Specifically", the researcher adds, "we showed that there is a type of lymphocyte that produces a substance called IL-17, which allows the cells of the adipose tissue, the adipocytes, to transform into fat and store the excess carbohydrates in our diet. Otherwise, this excess would cause imbalances in the blood," with harmful consequences for our health.
"This is a mechanism that, throughout evolution, has been essential for mammals to be able to build up energy reserves in anticipation of periods of food shortage," emphasises Veiga-Fernandes.
But we all know that the accumulation of fat in the body is currently one of the biggest health problems in the most developed countries, because the majority of the population never experiences calorie deficits and eats too many carbohydrates, storing unwanted fat. In fact, the process of lipogenesis is altered in several serious “modern life” diseases, such as cancer, metabolic syndrome and obesity.
Veiga-Fernandes suggests that the results obtained could, in the future, be used to combat the harmful effects of excess fat in adipose tissue, paving the way for the development of new drugs that inhibit lipogenesis.
It was Lydia Lynch, Principal Investigator at Princeton University, and also senior co-author of the new work, who invited the two researchers from the Champalimaud Foundation – Veiga-Fernandes and Miguel Rendas, second author of the study – to collaborate. "[The other co-authors] explored the processes by which gamma-delta lymphocytes control lipogenesis and we unravelled the circadian regulation of these same cells and of IL17”, sums up Veiga-Fernandes.
More precisely, the Portuguese contribution to the new work consisted in identifying how T-gamma-delta lymphocytes produce IL-17 following very precise biological rhythms. "We carried out studies of the circadian rhythm (day/night), of the "hour change" in gamma-delta T lymphocytes and of the consequent deregulation of IL-17 expression."
"It's as if these cells had a clock inside them that allows them to produce IL-17 at very specific times during the day [or during the night for mice, which are nocturnal animals], so that the production of fat by adipose tissue corresponds to the times when there is a greater availability of carbohydrates" from food, explains Veiga-Fernandes.
These timings are all the more important because IL-17 is a substance that promotes inflammation. If IL-17 were to be constantly produced, it could lead to harmful inflammatory diseases.
The first lesson to be learnt from the study, says Veiga-Fernandes, is that the immune system, which we normally associate with the response to infections and the fight against cancer, is also very important in regulating a fundamental aspect of our lives: our metabolism. "And the second thing, which is very important, is that this process is very finely regulated, it's a kind of Swiss watch." It should be said that the production of IL-17 is not induced by food, but that it coincides, possibly as a result of evolution, with the periods when we are most active.
Can this Swiss watch give the wrong time? "What our article also shows is that one of the most important factors in regulating this clock is exposure to light – or rather, the cycle of light and darkness, or circadian cycle", replies Veiga-Fernandes. This process is most likely mediated by the main light detection centre, located in the brain.
"Although in this study we didn't analyse in detail the factors that change time in these lymphocytes, it's very likely that the metabolism clock is influenced by changes in time zones or sleep patterns", the researcher explains. This happens in people who work shifts, or who are constantly jetlagged because they travel frequently for professional reasons. It can also happen in people with psychiatric illnesses or who have insomnia and eat and sleep after hours. "The biological rhythm, while being intrinsic, is not immutable," says Veiga-Fernandes. "It adapts our organism to changes in our environment and way of life," he adds.
Normally, when we change time zones sporadically, the immune system's clock is able to adapt. But constantly changing it causes the production of IL-17 to become asynchronous and can lead to cardiovascular disease, diabetes, fatty liver, cancer, etc.
"What happens very often with modern lifestyles is that we don't need to go to the other side of the Earth to break the clock and be unable to reset it," the researcher emphasises. “It's our behaviour that does it."
"It's very interesting," concludes Veiga-Fernandes, "that the association between our behaviours, our risk habits and changes in our immune system end up having such a big impact on our metabolism and quality of life. Because these changes influence every cell in our body, every organ, every tissue. In short, they largely define who we are."
Original paper here.
