Abstract

Objective: Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in CNS areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.

Research design and Methods: We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently we investigated the potential mechanism of action by determining sites of neuronal activation following ICV injection of PK2, the hypothalamic site of action of PK2 and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target we investigated the effect of chronic administration in lean and obese mice.

Results: Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake whilst anti-PK2 antibody increased food intake suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of alpha-MSH from ex-vivo hypothalamic explants. In addition ICV co-administration of the alpha-MSH antagonist agouti related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and bodyweight in lean and obese mice.

Conclusions: This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is partly mediated via the melanocortin system.