New research shows that an enzyme produced by macrophages (immune system cells) in fat tissue plays an essential role in the loss of metabolic health in people with obesity and might serve as a biomarker to help us identify those at the highest risk of fibrosis, inflammation and insulin resistance or type 2 diabetes associated with obesity. It also identifies a potential target for drugs that might prevent or reverse metabolic disease and could throw light on a long-unexplained paradox.

The research from the TVP group, working with International collaborators and published in Nature Metabolism, uses a variety of approaches and draws on insights from human genetics, human and mouse studies, fibro-inflammatory cells, molecular profiling and computational biology. It identifies the enzyme – Peptidase D, also known as Prolidase (PEPD) – is essential for the development, in people with obesity, of abnormal function in fat tissue, of fibrosis with inflammation and of insulin resistance.

The fact that people can live with obesity but remain metabolically healthy when others are metabolically unhealthy while not having obesity is a paradox for which this research provides a possible explanation. PEPD has two functions. Firstly, controlling collagen turnover helps to prevent its excess deposition (fibrosis), which can lead to insulin resistance and type 2 diabetes. Secondly, when secreted from macrophages into the blood, the same molecule can also act as an intercellular signal to exacerbate fibrosis and inflammation (i.e. the opposite effect). The researchers saw reduced PEPD activity in humans and mice with obesity, which leads to abnormally-functioning fat tissue and fibrosis. In addition, when this enzymatic function of PEPD is reduced, an increase in the secretion of PEPD from fat tissue macrophages appears to be triggered, which acts as a signal that promotes inflammation and insulin resistance. It is already known that the degree of fibrosis and inflammation in fat tissue might be a more critical risk factor for metabolic complications than the degree of obesity. This research also shows that variation in the gene for PEPD can mean that an individual can be more or less likely to develop metabolic complications if they have obesity.

The study provides a strong rationale for measuring serum PEPD in individuals with obesity to help identify those at the highest metabolic risk.

 

This research is a major effort from many laboratories through a broad international collaboration, including laboratories from Paris, Bielefeld, Nanjing, Girona, Valencia, Taiwan, Bari, Uppsala, London, New York, and Copenhagen. We are very thankful for the funding bodies that have supported this global collaboration, particularly the MRC, Wellcome Trust and the British Heart Foundation in Cambridge and the various agencies supporting our collaborators. 

 

 

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