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Br J Pharmacol. 2013 Jan;168(2):403-10. doi: 10.1111/j.1476-5381.2012.02191.x.

Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem.

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1
Section of Investigative Medicine, Imperial College London, London, UK.

Abstract

BACKGROUND AND PURPOSE:

Prokineticin 2 (PK2) has recently been shown to acutely reduce food intake in rodents. We aimed to determine the CNS sites and receptors that mediate the anorectic effects of peripherally administered PK2 and its chronic effects on glucose and energy homeostasis.

EXPERIMENTAL APPROACH:

We investigated neuronal activation following i.p. administration of PK2 using c-Fos-like immunoreactivity (CFL-IR). The anorectic effect of PK2 was examined in mice with targeted deletion of either prokineticin receptor 1 (PKR1) or prokineticin receptor 2 (PKR2), and in wild-type mice following administration of the PKR1 antagonist, PC1. The effect of IP PK2 administration on glucose homeostasis was investigated. Finally, the effect of long-term administration of PK2 on glucose and energy homeostasis in diet-induced obese (DIO) mice was determined.

KEY RESULTS:

I.p. PK2 administration significantly increased CFL-IR in the dorsal motor vagal nucleus of the brainstem. The anorectic effect of PK2 was maintained in mice lacking the PKR2 but abolished in mice lacking PKR1 and in wild-type mice pre-treated with PC1. DIO mice treated chronically with PK2 had no changes in glucose levels but significantly reduced food intake and body weight compared to controls.

CONCLUSIONS AND IMPLICATIONS:

Together, our data suggest that the anorectic effects of peripherally administered PK2 are mediated via the brainstem and this effect requires PKR1 but not PKR2 signalling. Chronic administration of PK2 reduces food intake and body weight in a mouse model of human obesity, suggesting that PKR1-selective agonists have potential to be novel therapeutics for the treatment of obesity.

PMID:
22935107
PMCID:
PMC3572566
DOI:
10.1111/j.1476-5381.2012.02191.x
[Indexed for MEDLINE]
Free PMC Article
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