title: Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Section of Investigative Medicine, Imperial College London, London, UK.
authors.forename: Kel
authors.initials: K
authors.lastname: Beale
authors.forename: J V
authors.initials: JV
authors.lastname: Gardiner
authors.forename: G A
authors.initials: GA
authors.lastname: Bewick
authors.forename: K
authors.initials: K
authors.lastname: Hostomska
authors.forename: N A
authors.initials: NA
authors.lastname: Patel
authors.forename: S S
authors.initials: SS
authors.lastname: Hussain
authors.forename: C N
authors.initials: CN
authors.lastname: Jayasena
authors.forename: F J P
authors.initials: FJ
authors.lastname: Ebling
authors.forename: P H
authors.initials: PH
authors.lastname: Jethwa
authors.forename: H M
authors.initials: HM
authors.lastname: Prosser
authors.forename: R
authors.initials: R
authors.lastname: Lattanzi
authors.forename: L
authors.initials: L
authors.lastname: Negri
authors.forename: M A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: S R
authors.initials: SR
authors.lastname: Bloom
authors.forename: W S
authors.initials: WS
authors.lastname: Dhillo
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects* / Q000502:physiology; D004435:Eating / Q000187:drug effects*; D005260:Female; D005768:Gastrointestinal Hormones / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009479:Neuropeptides / Q000008:administration & dosage*; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C525015:PKR1 protein, mouse; C525016:PKR2 protein, mouse; C486586:Prok2 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled