Macrophages in Visceral Fat Tissue Produce Inflammatory Signals that Accelerate Atherosclerosis

Visceral fat tissue is known to produce chronic inflammation via a range of mechanisms that rouse the immune system to futile, self-defeating action. Here researchers investigate the signals produced by macrophages of the innate immune system in fat tissue and their contribution to the progression of atherosclerosis. Atherosclerosis is the buildup of fatty deposits in blood vessel walls, the largest single cause of human mortality. It is a condition driven by macrophage dysfunction, as macrophages are responsible for clearing excess cholesterol, toxic forms of altered cholesterol, and cholesterol carriers such as LDL particles from blood vessel walls. The degree to which macrophages falter at this task determines the tipping point at which a small amount of cholesterol deposition can grow to become an atherosclerotic plaque.

One of the factors determining macrophage activity is their response to the signaling environment. Macrophages can adopt a variety of states depending on levels of various inflammatory signal molecules. The most useful state for clearing cholesterol is M2, an anti-inflammatory, pro-regenerative collection of behaviors. Inflammatory signaling tends to make macrophages adopt the aggressive M1 state optimized for hunting down pathogens, however, and these macrophages give up on cholesterol clearance. Thus the more inflammation, the less effort goes into to attempting to repair atherosclerotic lesions and the cholesterol deposits that will become atherosclerotic lesions.

In today's open access paper, researchers identify some of the more important signals emerging from macrophages in visceral fat tissue. They note that blocking these signals can remove the effects of fat tissue on the progression of atherosclerosis. A more practical approach is to avoid becoming overweight in the first place, but it is worth noting that as aging progresses, a state of chronic inflammation will arise regardless; visceral fat just makes it considerably worse. Solving the underlying causes of that chronic inflammation will be necessary. Even blocking the important signals is only a patch on the problem, and a patch that also tends to disable some of the necessary working of the immune system following injury and infection. That is not ideal!

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr-/- recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors.

By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.

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