Uroguanylin Pathway Could Be the Key to Feeling Full

Uroguanylin Pathway Could Be the Key to Feeling Full

The obesity epidemic is growing daily; worse, it seems to be accelerating. With the increased numbers of overweight and obese people comes a higher risk of those people suffering health complications associated with obesity, such as Type 2 diabetes. Research teams around the world are attempting to identify body processes that could be targeted by therapeutics to reduce appetite and therefore reduce obesity. One such research team, led by Scott Waldman with the Department of Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology at Thomas Jefferson University in Philadelphia, has identified a new potential target for therapeutics in their work with analyzing the mechanisms that control appetite in mice down to the molecular level.

In studying mice, Waldman’s research team discovered that when they took in nutrients from food, the cells of the gut released a precursor to a hormone known as uroguanylin (prouroguanylin). The precursor is secreted in the blood and travels through the bloodstream to the brain where it is converted to uroguanylin in the hypothalamus, a region of the brain that has been associated with a decrease in appetite. Once the uroguanylin is active, it binds to receptor proteins called GUCY2C receptors on the outside of nerve cells. The binding begins a process that signals to the mouse to decrease its food intake.

Waldman’s team showed that disrupting GUCY2C expression in mice impaired their normal appetite cycles by reducing satiation. When the pathway was interrupted and mice no longer felt full from eating, they engaged in hyperphagia — overeating. Unsurprisingly, this caused the mice to become obese and develop associated complications such as metabolic syndrome. This uroguanylin-GUCY2C pathway had been previously unrecognized.


According to Waldman and his research team, the findings show that it may be worth developing therapeutics that target the uroguanylin-GUCY2C pathway in order to control appetite and therefore reduce obesity and all the health complications that commonly accompany it, such as Type 2 diabetes. Randy Seeley and Matthias Tscöp of the University of Cincinnati, in an accompanying commentary, agreed with Waldman’s suggestion that this pathway be targeted for reducing obesity.

The article that accompanies the findings states that “Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut.” By targeting the hormones and processes involved in these hypothalamic circuits, the team has hopes that scientists may be able to produce therapeutics that activate the pathway and make people feel satiated by eating less food, which would work towards reducing obesity.

The team called obesity a pandemic in their paper, citing that it affects more than 300 million adults worldwide and is accompanied by an array of comorbidities including endocrine, metabolic, and oncologic diseases and decreased life expectancy. The economic burden of obesity, according to the researchers, exceeds $100 billion per year, and decoding the neural pathways that exist between the stomach and the brain may lead to treatments that control appetite and limit metabolic diseases such as diabetes.

The team’s findings are published on August 25, 2011 in the Journal of Clinical Investigation. The studies were supported by grants from the NIH and from Targeted Diagnostics and Therapeutics. Scott Waldman is the Samuel M.V. Hamilton Endowed Professor at Thomas Jefferson University.