title: Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice.
abstract: OBJECTIVE
  Orexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone.
  
  
  METHODS
  We generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts.
  
  
  RESULTS
  Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection.
  
  
  CONCLUSIONS
  Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Nguyen
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Katy
authors.initials: K
authors.lastname: Slack
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Lee
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Dana
authors.initials: D
authors.lastname: Boey
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ernie
authors.initials: E
authors.lastname: Yulyaningsih
authors.affiliation: Bone and Mineral Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ronaldo F
authors.initials: RF
authors.lastname: Enriquez
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Yan-Chuan
authors.initials: YC
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; Faculty of Medicine, University of NSW, Kensington, Sydney, NSW 2052, Australia.
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.affiliation: Neuroscience Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; School of Medical Sciences, University of NSW, Kensington, Sydney, NSW 2052, Australia; The Boden Institute of Obesity, Nutrition, Exercise & Eating Disorders, Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: amanda.salis@sydney.edu.au.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000235:genetics; D001835:Body Weight; D004399:Dynorphins / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000235:genetics*; D009765:Obesity / Q000235:genetics*
chemical_list: D009478:Neuropeptide Y; D004399:Dynorphins
keywords: Central feeding regulation; Endocrinology; Energy metabolism; Neuropeptide Y; Obesity