Alternating high-fat diet enhances atherosclerosis in mouse more than exclusively high-fat diet

6 September 2024

Little research has been done on the effects of alternating high-fat diets. Niels Riksen of Radboudumc and French colleagues investigated the effects of such a diet in mice. The diet was found to lead to more arterial calcification than a continuous high-fat diet.

 

In people with chronically excessive cholesterol levels, the immune system slowly slips into a kind of “inflammatory” state. This state stimulates the formation and growth of plaques in the blood vessels, a process called atherosclerosis (arteriosclerosis). Atherosclerosis causes cardiovascular diseases such as myocardial infarction or cerebral infarction. Exactly how that process works has been the subject of a great deal of research.

 

Hardly looked at yet

Niels Riksen, professor of Vascular Medicine at Radboudumc, wondered what the effect of alternating a high-fat and normal diet would be. “This has actually hardly been looked at yet,” he says, ”even though many people change their diet with some regularity, for example because they alternate diets. This can lead to fluctuations in blood fats and cholesterol. Even temporarily stopping cholesterol-lowering drugs can give such a fluctuation in blood cholesterol levels.” To investigate this, Riksen devised a study in mice and partnered with Prof. Hafid Ait Oufella of Paris. This research was funded in part by the Dutch Heart Foundation.

 

As much fat, but more calcification

The study was conducted using mice prone to atherosclerosis. One group of mice was fed a diet high in fat and cholesterol for a continuous period of time during the study, causing blood cholesterol levels to rise significantly. In the other group, a high-fat diet was alternated with a non-fat diet, with the total amount of fat between the two groups being the same; call it a yo-yo diet. The result, now published in Nature, is remarkable. Riksen: “In the yo-yo group, atherosclerosis struck much harder than in the group that followed a high-fat diet consecutively. In short, an alternating high-fat non-fat diet causes more plaque formation in the blood vessels than a continuous standard high-fat diet, despite the blood vessels being exposed to the same amount of cholesterol in total. The same amount of fat yet more plaques.”

 

Trained immunity

To see exactly where that difference comes from, the researchers dove deeper into the immune system. It turned out it was not due to changes in the acquired immune system - the part of the immune system that, after an initial infection with a virus or bacteria, remembers which pathogen has invaded and builds up a specific defense against it. Riksen: “For a long time we thought that the immune system consisted of an acquired immune system that can learn, and an innate immune system that you already inherit naturally at birth and does not change. In recent decades we have seen that this innate immune system can still adapt, that it can indeed respond to the environment. This is what we have since called trained immunity. It is precisely in this trained immunity that we see in the yo-yo group the changes that stimulate atherosclerosis.

 

Facilitator of arterial calcification

Riksen: “All blood cells originate from stem cells in the bone marrow. That is also where - through a process of division and specialization - all the different white blood cells come from. In one of the 'production lines,' a stem cell successively makes a myeloid precursor cell, myeloblast and neutrophil. What turns out? The switch diet causes those myeloid precursor cells to shoot into “inflammatory mode” and suddenly produce much more interleukin (IL-1β). That substance greatly boosts the production of both myeloid cells and neutrophils. And it is precisely those neutrophils that are the pacesetters of arterial calcification. The more neutrophils, the stronger that process of arterial calcification.”

 

Research in humans

To verify their findings, the researchers fished the neutrophils out of the mice's blood and silenced the explosion of interleukins. Riksen: “Then the production of myeloid cells drops back to normal levels and the inflammatory mode that stimulates arterial calcification also disappears.” Riksen emphasizes that this is research in mice, so it cannot automatically be applied to humans. Could a yo-yo diet, as well as, for example, temporarily stopping cholesterol-lowering drugs, also stimulate the process of calcification in humans? “That will only become clear with human research,” says Riksen. “For now, we have shown that an alternating high-fat diet stimulates arterial calcification more than a continuous high-fat diet. And now we also know that this mechanism works via trained immunity.”

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Paper in Nature: Alternate high fat diet enhances atherosclerosis by neutrophil reprogramming - Jean-Rémi Lavillegrand, Rida Al-Rifai, Sara Thietart, Théo Guyon, Marie Vandestienne, Raphael Cohen, Vincent Duval, Xiaodan Zhong, Daniel Yen, Mumin Ozturk, Yutaka Negishi, Joanne Konkel, Emmanuel Pinteaux, Olivia Lenoir, Jose Vilar, Ludivine Laurans, Bruno Esposito, Marius Bredon, Harry Sokol, Marc Diedisheim, Antoine-Emmanuel Saliba, Alma Zernecke, Clément Cochain, Jessica Haub, Alain Tedgui, Ziad Mallat, Nancy A. Speck, Soraya Taleb, Musa M Mhlanga, Andreas Schlitzer, Niels P. Riksen & Hafid Ait-Oufella

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