What could the correlation be between that third serving of scrumptious double-fudge macadamia slice ogling at you from the dish, and the risk of increased cardiovascular mortality? In other words, what are the molecular liaisons between bad nutrition habits leading to obesity, and cardiovascular problems?

With a similar question in mind, EVGN scientist Ziad Mallat from Unit 689 at INSERM (Paris) and colleagues from Toulouse, Leuven (Belgium) and the University Pierre et Marie Curie, set up some investigations that led to the following discovery. Using an animal model reproducing human atherosclerosis, they found that the lack of a hormone-like protein called leptin decreases the development of atherosclerotic plaques and protects the organism from this condition. Leptin is involved in energy expenditure and its levels rise when people gain weight. But, in addition, the scientists observed that the absence of either leptin or its receptor exerted a positive action on a specific population of immune cells– the family of lymphocytes called Treg – by modulating their responses during atherosclerosis progression. These cells, as INSERM scientist and EVGN scientific coordinator Alain Tedgui and Mallat himself had proven in the course of previous investigations, play a pivotal role in atherosclerosis: they reduce the inflammation and inhibit the activation of the immune system, thus behaving as internal protective sentinels. The current research was published in the October issue of Arteriosclerosis Thrombosis and Vascular Biology.

Besides promoting alterations in the metabolism of fats, triggering high blood pressure and causing the unbalance in sugar metabolism, obesity is also associated with a chronic inflammatory state. As such, it is the object of thorough investigations by scientists who try to figure out its role in atherosclerosis, another condition strictly related to inflammation. Leptin and its gene ob, on their side, have a well-characterized role in obesity. Coupling these two data, Mallat and colleagues decided to assess whether leptin was able to influence in any way the progression of atherosclerosis.

“The evidence we produced are clear-cut – explains first author of the study Soraya Taleb, from Unit 689 at INSERM – as they confirm that leptin acts as a commander in chief in modulating the evolution of atherosclerosis also via Treg cells. When induced in a mouse model of atherosclerosis, leptin deficiency protects the animal from developing the disease. Besides, it stimulates the production and function of T cells expressing Foxp3,a molecular trigger that tells the normal T lymphocytes hey, it’s time to wake up and become Treg”.

Molecules like hormones activate molecular pathways only after binding a proper lock. When it comes to leptin, the lock is a hormone-specific receptor that helps it to hit its biochemical target. What if the receptor is unavailable? “Actually we decided to address this question – says Taleb – using a mouse model unable to produce the receptor. We got striking results: we observed an increased number of Treg lymphocytes that were more efficient in their suppressing power”. On the contrary, when the leptin receptor signalling was left in place the scientists observed a boost in atherosclerosis progression.

“The role of leptin on atherosclerosis modulation – comments Ziad Mallat – is far from being completely clear, but clouds are vanishing now. Our results indicate the direct involvement of this substance in the immune responses taking place in atherosclerosis. Block leptin signalling and you’ll put a break to atherosclerosis by reducing the size of lesions. Eliminate its receptor and you’ll be activating the Treg sentries that keep inflammation at bay. Early that it might be, leptin is doomed to become a candidate target able to modulate the immune responses and to impact on atherosclerosis containment”. However, it should be manipulated with caution to avoid undesirable effects on metabolism.