Grant: Project Grant

Obese fat tissue shows abnormal accumulation of connective tissue components which is a hallmark of fibrosis. Fibrosis of fat tissue limits normal fat storage and fat tissue expansion in obesity and leads to inflammation, increased circulating fat and its accumulation to liver and other tissues. This abnormal fat accumulation pattern is tightly linked to development of insulin resistance and type 2 diabetes. Objective of this research proposal is to understand factors that may limit healthy tissue expansion. It focuses on a newly discovered obesity-linked gene, F13A1 (Factor XIIIA transglutaminase) and the how it may contribute to adipose tissue fibrosis and metabolic problems. Our results from cell culture studies suggest that Factor XIIIA normally regulates accumulation of a liver-derived protein fibronectin to fat tissue to increase fat cell numbers. However, plasma fibronectin in fat tissue can also limit cell growth in size and lipid storage and contribute to tissue fibrosis. Our animal studies show that mice that are lacking Factor XIIIA gene do not develop insulin resistance on a high fat diet. Results from lean and obese humans suggest that FXIIIA levels are increased in obesity associate with unhealthy metabolism and signs of pre-diabetes. The project involves a full examination of weight gain, fat tissue function and development of insulin resistance in two mouse models that lack either plasma fibronectin or FXIIIA. We will also investigate if defects in F13A1 gene exist in obese humans and if altered function is linked to unhealthy metabolism. Our work will allow us to better understand the mechanisms how type 2 diabetes develops in obesity. This will open possibilities to create therapeutics that can change the levels and activity of Factor XIIIA and plasma fibronectin in adipose tissue to allow its normal function.