Researchers have identified an enzyme in the brain that plays a key role in regulating how much food mice eat in one sitting, finding that deletion of this enzyme caused the mice to increase their food intake to the point of becoming obese.
The results may hint at a new therapeutic target for human obesity.
Obesity is associated with numerous diseases, yet available treatments for severe forms are lacking.
To gain more insights into the brain mechanisms that control meal size and thus body weight, Olof Lagerlöf and colleagues turned their attention to a pathway that has previously been associated with obesity.
One enzyme in particular, O-GlcNAc transferase (OGT), interacts with insulin, a hormone that plays a role in processing food.
When the team knocked out OGT in neurons of mature mice, which particularly affected the paraventricular nucleus (PVN) region of the brain, this had dramatic effects on their weight: within three weeks, their amount of fat tissue tripled.
In OGT knockout mice, daily food intake rapidly increased, plateauing at a level more than twice as high as for control mice.
If access to food was restricted to the same amount consumed by controls, the mice lacking OGT retained normal body weight.
Further investigation revealed that food normally activates OGT-expressing neurons in the PVN, but loss of OGT blocked activation of these neurons completely and significantly reduced the frequency at which they fired.
In contrast, stimulating OGT-expressing PVN neurons decreased cumulative food consumption over a 24-hour period.
A Perspective by Gary Schwartz discusses these findings in greater detail.