What Causes the Increased Appetite in PWS?

Dr. Tony Goldstone and Prof. Dick Swaab
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, Netherlands

Increased appetite and obesity are the most serious symptoms of Prader-Willi syndrome. Without adequate management, obesity leads to serious problems such as reduced mobility, high blood pressure, sugar diabetes and an increased risk of chest infections, which may eventually be life-threatening.

Our research is trying to find the cause of the increased appetite in PWS. It is hoped that such knowledge may eventually identify new ways to treat or prevent obesity, perhaps using drugs. It is thought that the problem in PWS is abnormal development of a part of the brain called the hypothalamus. The hypothalamus has been known for a long time to control appetite, as well as many other processes that are usually affected in PWS, such as growth and sexual development. However the hypothalamus is a very complex structure and contains many different brain chemicals, many of which may effect appetite.

In the last few years scientific research has identified which brain chemicals in the hypothalamus are particularly important in controlling appetite and body weight. However these studies have come mainly from animal experiments, and it is uncertain whether similar systems are as important in humans. It has been found that the hormone leptin is a major controller of these brain chemicals. Leptin is produced by fat cells in the body and circulates in the blood from where it is able to reach the brain. As people become fatter more leptin is found in the blood, while the levels fall when people stop eating. Leptin acts on nerve cells in the hypothalamus to alter their production and release of brain chemicals, leading to reduced appetite, increased metabolism and so helping to reduce body weight. Leptin reduces the production of chemicals in the brain that stimulate appetite and increases the production of chemicals that reduce appetite. Humans who are lacking leptin or are unable to respond to leptin due to rare genetic mutations (unrelated to the chromosomal abnormalities seen in PWS) have a very similar increase in appetite to that seen in PWS and develop obesity at a young age. This demonstrates that these pathways and chemicals are important in humans as well. The brain chemicals that control appetite are also regulated by factors other than leptin, such as hormones released when we eat food, sugar levels and stretching of the stomach.

People with PWS are not lacking in leptin and so focus passes onto the brain chemicals themselves. It is of course difficult to do such studies in humans and as yet it is not possible to analyse these chemicals while people are alive. Instead we must study the amounts of these brain chemicals using material that has been kindly donated for scientific research into PWS after people have died. Over the last 20 years, such brain material has been collected by Prof. Dick Swaab, through the Netherlands Brain Bank in Amsterdam, from all around the globe. Equally important the Brain Bank has gathered material from non-PWS patients of a similar sex and age to those with PWS, that can be used for comparison. This represents the only collection of such PWS material in the world and is in very limited supply. We have recently set up a programme in the United Kingdom, under the auspices of Dr. Tony Holland, Cambridge University and the United Kingdom PWS Association, in an attempt to increase the availability of such maerial. In this programme, families with PWS sign 'declarations of intent' for brain donation after death. Around 40 families have so far expressed an interest in such a programme. Increased awareness of our research around the world may also increase the access to such precious material, and we have recently been privileged to obtain material from a young girl with PWS who died in New Zealand. The kindness and thoughtfulness of people with PWS, their carers and families is much appreciated in this support of our research efforts, especially given the delicate nature of such work.

Using the PWS material available in Amsterdam we have been looking at two brain chemicals, called NPY and AGRP, that both stimulate appetite. They are found in the same nerve cells within a particular part of the hypothalamus, called the 'infundibular nucleus'. These cells project to other regions of the hypothalamus where they release the chemicals to stimulate appetite. We have found that rather than being high, these chemicals are reduced in the hypothalamus of people with PWS, as well as in obese people who do not have PWS. This suggests that the increased appetite in PWS is not due to increased activity of these NPY/AGRP nerve cells. Instead it seems that this part of the hypothalamus is responding normally to the obesity. The increased leptin in the blood acts to inhibit the production of these two brain chemicals in an attempt to reduce appetite. The cause of the increased hunger in PWS must therefore lie elsewhere in the hypothalamus, and be able to override this particular system.

We have previously shown that oxytocin, a chemical in another part of the hypothalamus (the paraventricular nucleus) that reduces feeding, is reduced in PWS and this may contribute to the increased appetite. Our future studies will look at some other brain chemicals that reduce appetite, including a-MSH, CART and CRH, to see if they might also be reduced in PWS. Apologies for all the chemical abbreviations but that is scientific shorthand for some very long words! In order to work properly, the brain chemicals that are released by nerve cells must act like a 'key' to bind to specific 'locks', called 'receptors', on the surface of other nerve cells. We will also look at the levels of these receptors in the hypothalamus to see if they may be missing in PWS. This might be another way in which abnormalities in the development of the hypothalamus might increase appetite.

We still have a long way to go before we fully understand how appetite is controlled in humans, let alone what has gone wrong in PWS. However we are slowly piecing together the jigsaw and in combination with the identification of the genes that are affected in PWS, we hope one day to understand and perhaps treat the obesity problems that can be so devastating. Identifying the brain chemicals that are not working properly is only one part of the equation, since drugs will be needed to target these pathways. Drug companies are involved in much research to develop such drugs given the increasing rate of obesity in the general population and this may also benefit people with PWS. The continued help from PWS families in our attempts to achieve these goals is most appreciated.

Dr. Tony Goldstone and Prof. Dick Swaab
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, Netherlands