UCF discovery could open door to obesity, diabetes treatments
(26 August 2009: VIDYYA MEDICAL NEWS SERVICE) -- At a time of alarming increases in obesity and associated diseases -- and fiery debates about the cost of health care -- a UCF research team has identified a new genetic mechanism that controls the body's fat-building process.
The discovery could open the door to new treatments for obesity and type 2 diabetes, and it has the potential to help hundreds of millions of people and dramatically cut health care costs.
A research team led by Pappachan Kolattukudy, director of UCF's Burnett School of Biomedical Sciences in the College of Medicine, found that a gene called MCPIP (Monocyte Chemotactic Protein-1 Induced Protein) controls the development of fat cells. Until now, a different protein, known as peroxisome proliferator-activated receptor gamma (PPAR gamma), has been universally accepted as the master controller of fat cell formation, known as adipogenesis.
The UCF findings give scientists a new direction for developing drugs that could benefit the more than 300 million people worldwide who are clinically obese -- and who have much higher risks of suffering from chronic disease and disability. In addition, it is projected that more than 300 million people will be diabetic by the year 2025.
Kolattukudy said MCPIP is potentially an ideal target for drugs that would prevent the body from becoming resistant to insulin and prone to type 2 diabetes.
"Our research has shown that MCPIP is a regulator of fat cell formation and blood vessel formation that feeds the growing fat tissue," he said. "Therefore, a drug that can shut down its function can prevent obesity and the major inflammatory diseases resulting from obesity, including diabetes and cardiovascular diseases."
The findings will be published in the October issue of the Journal of Biological Chemistry. An advance version is now available online on the journal's Web site.
Kolattukudy introduced MCPIP to living cells from mice that had been stripped of the PPAR gamma gene and found that the cells still completed the developmental process necessary to build fat.
His next step is to begin exploring chemical combinations to discover drugs that are effective at shutting down the novel gene. The development of new drugs that can block or slow down the formation of MCPIP likely would take several years. However, Kolattukudy is encouraged by the results of his research to date.
Kolattukudy, whose team in 2006 first identified the MCPIP gene as a contributor to heart disease, found its function as a fat inducer by focusing on its inflammatory influence.
Recent evidence has shown that the increased inflammation of fat cells causes them to become less sensitive to insulin, potentially triggering type 2 diabetes. A predominance of fatty tissue contributes to the inability to process insulin which, in turn, enables glucose or sugars to flow directly to the bloodstream instead of going into cells.
Arterial, venous or total mesenteric ischemia/reperfusion causes different types of injury?
It is known that I/R induces an inflammatory response deleterious to the organ involved but also to the system as a whole. Mesenteric ischemia occurs when the veins or arteries that supply blood to the intestine are obstructed. In transplants, the organ undergoes total (arterial and venous) I/R. Few available treatments exist. Greater knowledge of these conditions would aid in the search for new therapies. However, the precise nature of the response arises after venous, arterial or total ischemia is not fully understood.
A research article to be published on August 21, 2009 in the World Journal of Gastroenterology addresses this question. The research team led by Professor Guzman-de la Garza of the Autonomous University of Nuevo Leon, Mexico, used a rodent model of intestinal I/R to study the different inflammatory mediators that are associated with venous, arterial or total vascular occlusion. Most studies have so far concentrated on arterial ischemia, implicating molecules such as tumor necrosis factor-alpha (TNF-alpha) and adhesion molecules in the pathophysiology of the response to injury.
When these molecules, along with others, such as antithrombin III and endothelin-1, were measured after the different forms of intestinal I/R, it was clear that the patterns were different. Interestingly, venous ischemia caused greater injury than arterial ischemia, and total ischemia was associated with the most severe form of injury. Some molecules, such as TNF-alpha and antithrombin, were nicely correlated to injury severity, while others, such as endothelin-1, were not elevated at all after total ischemia.
Given the current tendency to use drugs that selectively block some of these molecules in the treatment of inflammatory diseases, this knowledge could be useful in designing specific therapies for each of the conditions associated to ischemia (venous occlusion, arterial ischemia, transplant procedures). Future studies will be needed to evaluate the clinical significance of these findings.
Reference: Guzmán-de la Garza FJ, Cámara-Lemarroy CR, Alarcón-Galván G, Cordero-Pérez P, Muñoz-Espinosa LE, Fernández-Garza NE. Different patterns of intestinal response to injury fter arterial, venous or arteriovenous occlusion in rats. World J astroenterol 2009; 15(31): 3901-3907
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