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Specific Loss of Adipocyte CD248 Improves Metabolic Health via Reduced White Adipose Tissue Hypoxia, Fibrosis and Inflammation

By July 3, 2019No Comments

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This week we profile a recent publication in EBioMedicine from the laboratory of
Dr. Edward Conway (pictured, centre) at the UBC Centre for Blood Research.

Can you provide a brief overview of your lab’s current research focus?

I am a professor of Medicine and Director of the Centre for Blood Research at UBC. The overall goal of my lab is to delineate the protective properties of cells that line and surround blood vessels, with a view to developing novel diagnostic and therapeutic approaches. Our current focus is on characterizing the structure and function of two cell-surface expressed proteins, thrombomodulin and CD248, both of which regulate inflammation, cell proliferation, and fibrosis. By using molecular/cell biologic techniques and genetically modified mice, in conjunction with human genetic studies, we are aiming to gain new insights into how these proteins impact on the risk of developing venous and arterial thrombosis, atherosclerosis, age-related macular degeneration, and type 2 diabetes.

What is the significance of the findings in this publication?

With chronic overeating and obesity, white adipose tissue undergoes inflammatory changes that promotes glucose intolerance, insulin resistance and the development of type 2 diabetes. The mechanisms by which a healthy adipocyte in white adipose tissue acquires a “diabetic” phenotype are poorly understood. In collaboration with Dr. Mikael Rydén and his Postdoc, Paul Petrus at the Karolinska Institute, we showed that a protein known as CD248 is highly expressed by white adipocytes, and that transcript levels of CD248 in adipose are tightly and positively correlated to obesity and insulin resistance in humans. In line with these findings, knockout of the Cd248 gene in mice renders them resistant to developing obesity-associated diabetes, protecting the adipose tissue from undergoing inflammatory and fibrotic changes. Moreover, by deleting the Cd248 gene from mice after they were already obese, we could reverse the type 2 diabetes, even while the animals still remained obese, and without any detectable adverse effects. Our findings indicate that CD248 is a newly identified “molecular switch” that controls the transition from healthy to unhealthy adipose. CD248 therefore might be a valuable predictive marker of type 2 diabetes, and more notably, a potential therapeutic target to reverse malfunctioning white adipose tissue to improve metabolic health and prevent/treat type 2 diabetes.

What are the next steps for this research?

Indeed, there are several “next steps”: Clinical studies are planned to assess the value of CD248 as a marker to predict who is at risk of developing diabetes and as a means of monitoring the effectiveness of current treatments for diabetes. We are naturally exploring different approaches to suppress CD248 expression, using antibodies and gene silencing techniques, that will be tested in the mouse models. It’s also crucial that we gain an understanding of how CD248 functions as a “molecular switch”, as this will provide new strategies to prevent and/or treat diabetes and likely other inflammatory diseases. Based on recent cell biologic and intracellular signalling data, we have clues as to how CD248 might be functioning by interacting with other membrane-associated proteins. Studies are underway to fully characterize these interactions and their relevance. With this information and a newly developed in vitro adipose “organoid” system that replicates what happens to fat in the body, we will also screen libraries of compounds to identify those that interfere with the function of CD248. Lead compounds will then be further validated and modified for in vivo testing in mouse models. Although we are still some distance from a new treatment, we believe that it is realistic and achievable goal.

This research was funded by:

The Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, a Killam Scholarship, Morphotek Inc., the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Diabetes Foundation and the Diabetes Research Program at the Karolinska Institutet.

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