Dominique Langin, from Toulouse, has just published a study which opens the way to new drugs against obesity and its complications, notably cardiovascular diseases.
How to activate brown fat, “heating” the cold body, and a factor in good cariovascular health? The team from Toulouse Dominique Langin carried out a study, published on November 19 in the journal Cell Metabolismwhich clearly establishes the brown fat cell activation pathway. This route, indicates Inserm, is “a way to burn fat and allow weight loss”.
Dominique Langin is a university professor, hospital practitioner at Toulouse III-Paul-Sabatier University and director of the Institute of Metabolic Cardiovascular Diseases (obesity, diabetes, atherosclerosis, renal and heart failure, etc.), 300 people, 14 research teams .
DR
Before talking about the virtues of brown fat, how can we differentiate it from so-called white fat, to put it simply, the fat on our bulges?
We all know white fat, also called adipose tissue. This is where we store energy and remobilize it when our body needs it. All mammals have white fat, birds too, it is strictly essential for a healthy life. What poses a problem is excess, which leads to obesity, and to a certain number of disorders in the body which will promote cardiovascular diseases, liver diseases and diabetes.
And everyone has them?
Yes, and you can be sick from excess fat, as well as from lack of fat.
It is, for example, essential during pregnancy. The colonization of the Pacific Islands, which started from Southeast Asia and ended on Easter Island, would not have been possible without our fats! We had to constantly mobilize energy.
Does everyone have brown fat?
Brown fat is specific to mammals. Its original function is to produce heat to control body temperature. All warm-blooded mammals have different mechanisms in their body to maintain this temperature: white fat, which has an insulating role, a sort of “down jacket” effect, and brown fat which is a “radiator”, capable to make heat.
Brown fat has been known for a long time; the first description dates from the end of the 19th century. In the second half of the 20th century, we discovered this function which plays in adaptation to cold.
The first study was carried out on hibernating animals in the Pyrenees: marmots accumulate a lot of white fat during the summer, burning it during hibernation, when their body temperature drops to 6°C. When you wake up, it is brown fat that will raise your body temperature from 6°C to 37°C by burning fat.
Another example: the newborn. At birth, it is brown fat that will burn fat so that it can adapt to temperatures lower than what it experienced in utero.
Everyone has brown fat, but it was thought that in humans it disappeared very quickly after birth. We have it more or less, it represents at most a few percent of all fats, and is located very discreetly and very precisely at the level of the neck, the vertebrae, on the adrenal glands, above the kidneys.
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There are two constants, however: the older we get, the less brown fat we have, regardless of our body mass index. Finally, the higher the body mass index, the less brown fat we will have, knowing that the brown color is linked to function: it is due to small elements in the cell which are factories for producing heat, they are hyperactive.
Hence the idea that if we manage to reactivate these factories, we can “destock” fat in heat, and therefore lose weight. At the moment, we don't know if we will succeed. In its “natural” state, the physiological activator of this system is cold. For example, swimmers in cold water will have more brown fat, and overall, whenever we shiver, we activate brown fat. But can we reactivate it in a context of obesity or in elderly subjects?
“The first objective is not to make people lose weight”
Is this the subject of your research?
Our research focuses on fat mobilization: how stored fat will be remobilized for use. In brown fat, two enzymes are known to be involved.
But what is the activation pathway? If we want to develop strategies and drugs, we need to know whether we directly target the brown cell to power the “factories” that produce energy and heat, the mitochondria, or whether we need to take indirect routes. There was doubt since 2017.
To do this, we removed the two enzymes only in the brown cell, in mice. Those who no longer have the enzymes cannot control their body temperature. It is obvious that the mobilization of fats inside brown cells is fundamental. To carry out this study, we approached Professor Carpentier's group in Sherbrooke, Canada, which, using imaging techniques, was able to measure the heat production activity in brown adipose tissue. We were thus able to show that in mice which no longer had enzymes, we no longer had heat production.
It is therefore necessary to target brown adipose tissue to make it work and produce heat.
Another objective of our research is to understand the pathways by which brown adipose tissue is transformed into white fat, when it is not used.
And enzymes are like keys that start the engine?
Yes, if we imagine that the “car” is the brown cell.
The goal now is to produce medicines?
The objective is to trigger, from the surface of the brown cell, a series of events which will activate the enzymes.
The targets will be receptors present on the surface of the cell, so that if there is a drug, it can circulate in the blood and reach the receptors.
Do we know how to do it?
Yes, in animal models: we inject a molecule which mimics the effect of the nervous system which activates the brown cell in the cold. But this class of medication cannot yet be used in humans due to side effects, or because it is not yet effective and precise enough in its action.
Other types of targets are currently being studied. Academic laboratories are working on molecules that act on receptors, as well as private laboratories and start-ups.
Many studies show that people who have brown adipose tissue are in better cardio-metabolic health than those who don't have it. The first objective is not to make people lose weight but to reduce the risk of developing a heart problem, a liver problem, and to prevent diabetes.
