Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake.
OBJECTIVE
Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.


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 after 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, whereas 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-melanocyte-stimulating hormone (alpha-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the alpha-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight 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 mediated partly via the melanocortin system.
Gardiner
James V
JV
Department of Investigative Medicine, Imperial College London, London, UK.
Bataveljic
Attia
A
Patel
Neekhil A
NA
Bewick
Gavin A
GA
Roy
Debabrata
D
Campbell
Daniel
D
Greenwood
Hannah C
HC
Murphy
Kevin G
KG
Hameed
Saira
S
Jethwa
Preeti H
PH
Ebling
Francis J P
FJ
Vickers
Steven P
SP
Cheetham
Sharon
S
Ghatei
Mohammad A
MA
Bloom
Stephen R
SR
Dhillo
Waljit S
WS
D000818:Animals; D004305:Dose-Response Relationship, Drug; D002149:Energy Intake / Q000187:drug effects*; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D012333:RNA, Messenger; C513686:prokineticin 2, rat