Team Discovers a Chemical Pathway that Causes Mice to Overeat and Gain Weight

By Mark Schrope

Researchers from The Scripps Research Institute who are studying how body temperature and energy metabolism are regulated have discovered a pathway that appears to play a critical role in the onset of obesity. Further study of the pathway could lead to better understanding of the physiological foundation of obesity in humans and even the discovery of new treatments for the condition.

The work is being published February 16 in an online edition of the Proceedings of the National Academy of Sciences.

The Scripps Research team, led by neuroscientists Manuel Sanchez-Alavez and Tamas Bartfai, discovered that mice genetically altered to lack a molecule known as the EP3 receptor tend to be more active during their normal sleep cycle and to eat more. In the study, this led to weight increases of up to 30 percent relative to mice with the receptors.

The EP3 receptor is one of four types of receptors for prostaglandin E2 (PGE2), the most important inflammatory mediator that controls a variety of physiological functions including fever, fertility, and blood pressure. The most common anti-inflammatory and analgesic treatments like ibuprofen are aimed at reducing PGE2 signaling at all four prostaglandin receptors.

The absence of EP3 receptors has long been known to prevent fever response in mice, and it was this effect that the Scripps Research team was originally studying. Previous research on mice lacking the receptors had focused on fever inhibition until mice were about three months old. The team wanted to better understand the process by studying if fever inhibition continued later in life.

When the mice were four to five months old, the researchers made a startling discovery. The older mice still did not develop fever, but the researchers noticed that these mice were gaining weight.

"The experimental mice were clearly getting heavier than their wild type litter mates, the control mice," says Sanchez-Alavez. "We realized there was something interesting going on with these animals, so we started watching their behavior at night and during the day."

During continuous monitoring of temperature and motor activity, the researchers realized that the mice without the EP3 receptors were more active during the light hours—the nocturnal mice's "night"—and, more importantly, were eating during this time. The increased activity led to higher body temperatures, but this did not burn enough extra calories to balance the additional eating, so the mice weighed 15 to 30 percent more than control mice.

Determining why the lack of EP3 receptors causes increased activity and eating will likely take a great deal of experimentation. "It's a very complex phenomenon to explore," says Sanchez-Alavez. He notes that the next step in the research will be to determine whether the obese phenotype observed in the EP3 receptor deficient mice is dependent on the lack of EP3 in the central nervous system and/or peripheral organs, as EP3 is expressed in both locations.

The research has interesting implications for scientists' understanding of appetite regulation. PGE2 is known to stimulate the release of leptin—an important hormone secreted by white fat cells and a suppressor of appetite. However, in this model, lack of EP3 did not prevent leptin increase. "Something is happening there in that circuit," says Sanchez-Alavez. "The PGE2 and leptin may be interacting and controlling eating behavior."

Bartfai, who is chair of the Molecular and Integrative Neuroscience Department, director of the Harold L. Dorris Neurological Research Center, and member of the Skaggs Institute for Chemical Biology at Scripps Reseearch, notes, "Inflammation as part of the obesity and metabolic syndrome is being recognized to an increasing degree. These data directly couple the lack of a particular type of inflammatory signaling via EP3R with leptin and insulin increase, glucose tolerance, and white fat accumulation, and thus may provide a very important animal model for determining the importance of inflammation in obesity and in the conversion of obesity to type 2 diabetes."

Ultimately, better understanding of the role of EP3 receptors in feeding and obesity could lead to the development of treatments that could prevent or reverse these conditions.

Along with Sanchez-Alavez and Bartfai, Izabella Klein, Sara Brownell, Iustin Tabarean, Christopher Davis, and Bruno Conti, all of Scripps Research, were authors on the paper, "Night eating and obesity in the EP3R deficient mouse." See http://www.pnas.org/cgi/content/abstract/0611209104v1.

Send comments to: mikaono[at]scripps.edu

"The experimental mice were clearly getting heavier than their wild type litter mates, the control mice," says Research Associate Manuel Sanchez-Alavez.

"Inflammation as part of the obesity and metabolic syndrome is being recognized to an increasing degree," says Professor Tamas Bartfai.