Investigation of the mechanisms of chemerin processing by adipocyte-derived proteases.

Fat tissue is the largest endocrine organ in the body and releases hormone-like proteins called adipokines that regulate metabolism, the immune system and reproduction. We have identified a new adipokine, chemerin that is needed for proper development of fat cells. Additionally, chemerin promotes insulin resistance in muscle and may contribute to inflammation in many human conditions including obesity, polycystic ovarian syndrome, inflammatory skin diseases, multiple sclerosis, inflammatory bowel diseases and arthritis by recruiting immune cells to sites of tissue injury. Chemerin is released from cells as an inactive molecule (prochemerin). At sites of tissue injury, enzymes called proteases convert (process) prochemerin to active (functional) chemerin products. Other proteases can degrade chemerin and end the action of the functional protein. We have discovered that fat cells produce active chemerin. This indicates that fat cells: must release proteases that process prochemerin and may be an important and modifiable source of chemerin in the body. The goal of our work is to perform cell and animal studies to: 1) identify the fat cell proteases that activate prochemerin and degrade chemerin, 2) quantify the functional activity and identify the chemerin products produced by fat-cells and 3) determine if protease processing of prochemerin increases the blood levels of chemerin in obesity, a condition characterized by excess fat tissue and low level inflammation. Understanding how fat cells process prochemerin or chemerin may serve as the basis for blocking chemerin activation or increasing chemerin degradation. This could have health benefits by reducing the inflammatory or insulin resistance effects of chemerin in human diseases, notably obesity, which in Canada afflicts about 23% of the adult population and is a major cause of disability and premature death.