Investigation of the role of prokineticin 2, a newly identified potent inhibitor of food intake

Obesity is the major cause of early death in the UK, prematurely killing 1000 people per week. Despite great advances in knowledge, many of the factors which regulate appetite and body weight are unknown and to date there are no truly effective medical treatments for obesity. Evidence suggests that the recently identified novel chemical transmitter in the brain known as prokineticin-2 (PK-2) is important in appetite regulation. I will investigate the role of PK-2 in the control of appetite and the development of obesity. I will examine if PK-2 levels in the brain change in response to obesity and fasting. I will also determine the types of brain cells activated by PK-2 and also the effects of PK-2 in different regions of the brain. I will also investigate if increasing or decreasing the amount of PK-2 in the rat brain affects food intake. These studies are important as they will determine the mechanisms in the brain by which PK-2 affects food intake and may provide the basis for new drugs for the treatment of obesity.

Prokineticin 2 (PK-2) is a newly identified hypothalamic neurotransmitter. PK-2 expression in the hypothalamus is highest in satiated and lowest in fasted animals. In pilot studies I have shown that PK-2 is the most potent inhibitor of food intake yet identified and that immunoblockade of PK-2 by intracerebroventricular administration of anti-PK-2 IgG increases feeding. Together, these data suggest that PK-2 has a physiological role in the regulation of food intake.

To determine the role and physiological importance of PK-2 in the control of appetite, I will:
1. Determine the responsiveness of PK-2 expression to specific alterations in energy balance.
2. Investigate the hypothalamic site of action of PK-2 and the neuronal pathways involved in PK-2 signalling.
3. Investigate the effects of PK-2 on long-term weight regulation in rats by over and under expression of hypothalamic PK-2 using adeno-associated virus mediated gene transfer.

Together, these experiments will help to determine the physiological importance of PK-2 in the hypothalamic regulation of food intake and may identify it as a useful target in the treatment of obesity.