Dr. Cai previously discovered that the “fullness” signal hormone CCK is present at normal levels in PWS but apparently ignored, and even adding more is ineffective. To understand why, he will proceed with advanced brain imaging techniques to identify which cells in which brain locations are affected, and he will attempt to stimulate them using other means.
Prader–Willi Syndrome (PWS) is a genetic disorder that causes constant hunger and can lead to severe obesity in later childhood. Surprisingly, after a meal, people with PWS have normal level of satiation (feeling full) hormones cholecystokinin (CCK), just like people without the disorder. This suggests the problem may not be with the satiation signals, but with how the brain processes those signals—essentially, the brain doesn’t "hear" the message to stop eating.
We still don’t fully understand how the brain controls appetite in PWS. Mutations in a gene called Magel2 are linked to many of the eating and metabolic problems seen in this condition. To study the underlying mechanism, scientists use special mice that don’t have the functional Magel2 gene (called Magel2-null mice), which show similar problems with appetite as people with PWS. In our research, we found that giving CCK to Magel2-null mice does not reduce their food intake—just like in humans with PWS. This confirms that these mice are a good model for studying how the brain fails to respond to appetite-control signals in PWS.
Our project has three main goals:
Aim 1: Look across the entire brain to identify regions that have altered number of neurons responding to CCK in Magel2-null mice.
Aim 2: Identify neurons in which brain regions involved in satiation control are not working properly in live animals.
Aim 3: Test whether we can target neurons in these specific brain regions to help control appetite in these mice.
If successful, the next step is to determine whether a similar neural mechanism is impaired in PWS and to develop drugs that target these neural substrates to control appetite. This research will identify new druggable neural targets and could lead to new treatments—such as specific drugs or other therapies—that help people with PWS manage their hunger by restoring proper appetite control. This could improve quality of life for individuals with this challenging disorder.