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The obesity-induced macrophage: a new player in atherosclerosis development

Final Report Summary - MACOBESITY (The obesity-induced macrophage: a new player in atherosclerosis development)

Obesity is reaching epidemic proportions and is an independent risk factor for the development of cardiometabolic diseases such as type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and to atherosclerosis, the main cause of cardiovascular diseases. A key event in obesity is the recruitment of a type of immune cell called “macrophage” to the adipose tissue. These macrophages differ from resident adipose tissue macrophages and are pro-inflammatory, possibly contributing to systemic low grade inflammation known to play a role in type 2 diabetes, NAFLD and atherosclerosis. This project aims to elucidate the interaction between inflammatory macrophages in the adipose tissue and the development of cardiometabolic diseases.

Dr. Wouters showed that inflammatory macrophages in adipose tissue produce factors that promote the recruitment of other immune cells using experimental models. These immune cells (neutrophils and monocytes) were shown to infiltrate the liver and to contribute to the worsening of NAFLD. Interestingly, these macrophages did not affect the development of atherosclerosis. Also in humans, dr. Wouters found that inflammatory macrophage numbers in adipose tissue were associated with circulating monocytes. Furthermore, using human adipose tissue and liver biopsies, a clear relation was found between inflammatory macrophage markers and factors that promote immune cell recruitment and with inflammatory markers in human liver.

In addition, Dr. Wouters has identified that another immune cell type, i.e. Natural Killer (NK) cells, may play an important role in the development of inflammation in visceral adipose tissue and concomitant type 2 diabetes. First, he showed in adipose tissue biopsies from lean and obese men that NK cells in blood are associated with adipose tissue inflammation. Next, he measured blood NK cells from 60 abdominally obese men and found that NK cells are involved in the causal relation between enlarged adipose tissue, inflammation, and insulin resistance, the major risk factor for type 2 diabetes. Finally, Dr. Wouters confirmed these results in the “Maastricht Study”, a large human cohort study in Maastricht (The Netherlands), where he measured immunological events in the blood of more than 1100 individuals with our without type 2 diabetes. Dr. Wouters will continue to investigate the inflammatory events in this large study to further identify the links between obesity, NAFLD, type 2 diabetes and cardiovascular diseases.

Dr. Wouters’ research continues to focus on the role of innate immune cells on the development of cardiometabolic diseases. He is now investigating the role of glucose consumption in activated macrophages during the formation of so-called advanced glycation endproducts (AGEs). AGEs are sugar-modified proteins that can induced inflammation and are suspected to cause cardiometabolic diseases.

Despite the clear role of inflammation in the development of cardiometabolic diseases, there are currently no effective therapies targeting the inflammatory component of these conditions. The results of this project identify causal pathways of inflammation, enabling to develop new therapeutic strategies for targeting the causes rather than the consequences of metabolic inflammation.