Regulation of expression of Prader-Willi syndrome region genes in the hypothalamus by nutritional and hormonal signals

The cause of the severe obesity characteristic of patients with Prader-Willi syndrome (PWS) is unknown. In the past few years however, there has been an explosion of information regarding the factors involved in the control of bodyweight. In particular, the hormone leptin, which is produced by fat, and a group of molecules in the brain called the melanocortins have been shown to respond to differing fat and nutrient levels in the body, highlighting this pathway as important for the normal control of food intake. To date, there has been no firm link between this pathway and genes in the PWS region. However, in preliminary studies using mice that have been fasted and mice with no melanocortin molecules, we have shown that there is reduced expression of many PWS genes in their brains. The fact that PWS genes can be controlled by signals relevant in controlling bodyweight is a novel observation and one which demands further exploration. We will attempt to show, using other obese mouse models, as well as using techniques allowing us to examine very minute and specific brain regions, which of these signals are important in controlling PWS gene expression.

Relevance Statement: We have shown, for the first time that the expression of some PWS region genes in the brain is regulated by nutritional and hormonal signals. This implies that one or more of these genes may be actively involved in the regulation of appetite and food intake. It has often been assumed in the past that the obesity of PWS might relate to some fundamental brain developmental defect that would be essentially irreversible. If it turns out the PWS gene products are dynamically involved in the control of appetite, this gives the hope that once the critical element is identified, it could potentially be therapeutically manipulated.

Funded Year:


Awarded to:

Stephen O'Rahilly, Ph.D. Professor and Head, Department of Clinical Biochemistry




University of Cambridge

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