Background: The novel peptide prokineticin-2 (PK2) has recently been implicated in the regulation of a number of physiological processes; including regulating gastrointestinal motility, spermatogenesis, neurogenesis and circadian rhythms. PK2 is a cysteine rich protein which mediates its effects via the prokineticin receptors which are expressed in several hypothalamic nuclei known to regulate food intake. We therefore hypothesised that PK2 may be an important endogenous regulator in appetite regulation.
Methods/results: ICV administration of PK-2 reduced food intake by up to 80% in ad libitum fed rats. PK-2 is at least 10-fold more potent than α-melanocyte stimulating hormone (α-MSH), the most potent endogenous hypothalamic anorectic agent presently known. This data suggests that PK-2 is the most powerful inhibitor of food intake yet discovered. We have also shown that immunoblockade of PK-2 by ICV administration of anti-PK-2 IgG increased feeding and fasting reduces hypothalamic PK-2 mRNA expression. In addition, intraventricular administration of PK-2 in rats resulted in neuronal activation, indicated by c-Fos protein expression in the supraoptic nucleus, arcuate nucleus, paraventricular nucleus and anterior hypothalamic areas. These areas are important in appetite regulation and direct injection of PK-2 in to these hypothalamic regions caused a reduction in food intake. This suggests that the anorectic effects of PK-2 may therefore be mediated via these hypothalamic areas. Peripheral administration of PK-2 twice daily for 5 days resulted in a significant reduction in food intake and a dramatic fall in body weight in both lean and obese mice.
Conclusions: Our findings suggest that endogenous PK-2 plays a physiological role in appetite regulation. We have identified PK-2 as a novel effective target for the treatment of obesity.