Potential new therapeutic target for obesity

Sep 25 2007

A hormone system linked to reducing food consumption appears to do so by increasing stress-related behaviors, according to a new study.

Mediated by a hormone receptor protein known as the corticotropin-releasing factor type 2 (CRF2) receptor, the system has attracted recent interest for its role in regulating food intake, say Vaishali Bakshi and Ned Kalin, professors in the Department of Psychiatry at the University of Wisconsin-Madison School of Medicine and Public Health.

"With the increasing focus on obesity, people are interested in finding targets that can be used to develop drugs that will reduce appetite and food intake without a lot of side effects," Bakshi says.

Previous studies have shown that activation of this receptor decreases the amount of food voluntarily eaten by hungry rats, an effect called induced anorexia. This finding led some researchers to suggest that the CRF2 receptor system might be a promising target for therapies to combat obesity.

However, the new study, appearing Sept. 26 in the Journal of Neuroscience, shows that CRF2 receptors in a single brain region, the lateral septum, mediate both feeding and behaviors associated with stress, suggesting this protein may not be an ideal therapeutic target.

By selectively stimulating the CRF2 receptors in the lateral septum, Bakshi and her colleagues found that the treated rats ate less overall - roughly half as much as untreated rats - because they spent less time at it.

"The reason that the rats were eating less after having CRF2 receptors stimulated in the lateral septum was because instead of eating they were spending most of their time exhibiting stress-like behaviors," such as excessive grooming, which Bakshi says has been proposed to represent a type of coping behavior.

In addition, the eating suppression may be secondary to the apparent stress-inducing effects of the receptor. "We found anxiety-like responses at smaller doses than those required to get the reduction in feeding," Bakshi says. "In terms of the chicken and the egg, it suggests that maybe the stress comes first and that the reduction in feeding comes second."

The role of CRF2 receptors in stress responses does not come as a complete surprise, Bakshi says, because the related protein CRF1 receptor exerts similar influences in a different brain region and has been studied for its involvement in anxiety disorders and clinical depression.

However, the finding does suggest that the CRF2 receptor pathway is not likely to be a good choice for the hoped-for obesity treatment.

"This is a cautionary tale," says Bakshi. "We're refuting a global statement that CRF2 stimulation reduces ingestive behavior without eliciting stress-like effects."