Appetite and energy expenditure, at their most basic level, are controlled by two sets of neurons in the hypothalamus. These are the neuropeptide Y/Agouti Related Protein (NPY/AgRP) neurons and the proopiomelanocortin (POMC) neurons. The NPY/AgRP neurons make the neuropeptides NPY and AgRP which are appetite stimulatory and the POMC neurons make POMC which is further processed to neuropeptides that are appetite suppressive. These neurons are regulated by two hormones, leptin and insulin.
While the Prader-Willi critical region on chromosome 15 includes a number of genes which are either lost or not expressed in the disease, much of the phenotype of PWS can be attributed to the loss or lack of expression of one gene, SNORD116, which regulates the activity of a number of other genes. In animal models when this gene is knocked-out or lost, among other changes, the
NPY/AgRP neurons produce substantially more NPY neuropeptide, substantially stimulating appetite. Interestingly, in animal models, when SNORD116 is knocked-out only in the NPY/AgRP neurons, the animals still show most of the PWS phenotype. It would appear that hyperphagia in PWS is driven by dysregulation of the expression of neuropeptides in the NPY/AgRP neurons.
Leptin interacting with its receptor in the NPY/AgRP neurons, or insulin interacting with its receptor triggers a cascade, the molecular end-point of which is thought to be the opening of the K ATP channel, resulting in diminished expression and secretion of NPY. Treatment with DCCR can directly open the K ATP channel in these neurons, reducing the synthesis and secretion of the appetite stimulatory neuropeptides, NPY and AgRP and, thereby, reducing hyperphagia.
Aggressive behaviors are a common feature in older adolescent and adult patients with PWS. These behaviors are thought to be associated with the dysregulation of γ-aminobutyric acid (GABA) signaling. GABA is the primary inhibitory neurotransmitter in the central nervous system. It has a principle role in reducing the excitability of neurons. GABA is also directly responsible for the regulation of muscle tone.
Because several of the genes that encode subunits of the GABA receptor are in the Prader-Willi critical region on chromosome 15, their expression is substantially reduced resulting in PWS patients having low GABA receptor numbers.
In PWS patients when the relationship between in-vivo brain GABA and emotion and behavior we investigated, it was found that GABA levels were significantly lower in the PWS patients who had clinically significant emotional and behavioral problems compared to both subjects without PWS and to PWS patients who did not have emotional and behavioral problems. GABA levels were negatively correlated with the extent of behavioral problems as well as temper outbursts.
In neurons with GABA receptors (GABAnergic neurons), diazoxide and an agonist of the GABA receptor modulated the excitability and activity of the neurons in a similar manner. Treatment with diazoxide and a GABA receptor agonist appeared to amplify the effect on excitability of the GABAnergic neuron.
In the context of low GABA and low GABA receptor numbers, as found in PWS, treatment with DCCR may amplify GABA’s effect on GABAnergic neuron, and thereby limit the aggressive and other behavioral complications of PWS.
It is clear that the K ATP channel is a central regulatory point of fatty acid biosynthesis and fat oxidation. The channel exerts coordinate control over these processes in adipocytes, hepatocytes and other tissues that make or store fat, and appears to function as a key step in the feedback regulation of fatty acid biosynthesis by long-chain acyl CoAs. Agonizing the channel in adipocytes results in highly selective loss of body fat, and in hepatocytes, it results in reduced synthesis and secretion of triglyceride and cholesterol rich lipoprotein particles.