title: Hypothalamic control of bone formation: distinct actions of leptin and y2 receptor pathways.
abstract: Leptin and Y2 receptors on hypothalamic NPY neurons mediate leptin effects on energy homeostasis; however, their interaction in modulating osteoblast activity is not established. Here, direct testing of this possibility indicates distinct mechanisms of action for leptin anti-osteogenic and Y2-/- anabolic pathways in modulating bone formation.
  
  
  BACKGROUND
  Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient ob/ob and Y2 receptor null mice. Similar elevation in central neuropeptide Y (NPY) expression and effects on osteoblast activity in these two models suggest a shared pathway between leptin and Y2 receptors in the central control of bone physiology. The aim of this study was to test whether the leptin and Y2 receptor pathways regulate bone by the same or distinct mechanisms.
  
  
  METHODS
  The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2-/- ob/ob double mutant mice, to determine whether leptin and Y2 receptor deficiency have additive effects. Interaction between leptin excess and Y2 receptor deletion was examined using recombinant adeno-associated viral vector overproduction of NPY (AAV-NPY) to produce weight gain and thus leptin excess in adult Y2-/- mice. Cancellous bone volume and bone cell function were assessed.
  
  
  RESULTS
  Osteoblast activity was comparably elevated in ob/ob, Y2-/-, and Y2-/- ob/ob mice. However, greater bone resorption in ob/ob and Y2-/- ob/ob mice reduced cancellous bone volume compared with Y2-/-. Both wildtype and Y2-/- AAV-NPY mice exhibited marked elevation of white adipose tissue accumulation and hence leptin expression, thereby reducing osteoblast activity. Despite this anti-osteogenic leptin effect in the obese AAV-NPY model, osteoblast activity in Y2-/- AAV-NPY mice remained significantly greater than in wildtype AAV-NPY mice.
  
  
  CONCLUSIONS
  This study suggests that NPY is not a key regulator of the leptin-dependent osteoblast activity, because both the leptin-deficient stimulation of bone formation and the excess leptin inhibition of bone formation can occur in the presence of high hypothalamic NPY. The Y2-/- pathway acts consistently to stimulate bone formation; in contrast, leptin continues to suppress bone formation as circulating levels increase. As a result, they act increasingly in opposition as obesity becomes more marked. Thus, in the absence of leptin, the cancellous bone response to loss of Y2 receptor and leptin activity can not be distinguished. However, as leptin levels increase to physiological levels, distinct signaling pathways are revealed.
authors.affiliation: Bone and Mineral Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, Sydney, Australia. p.baldock@garvan.org.au
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
authors.forename: Susan
authors.initials: S
authors.lastname: Allison
authors.forename: En-Ju D
authors.initials: EJ
authors.lastname: Lin
authors.forename: Michelle
authors.initials: M
authors.lastname: Couzens
authors.forename: Dana
authors.initials: D
authors.lastname: Boey
authors.forename: Ronaldo
authors.initials: R
authors.lastname: Enriquez
authors.forename: Matthew
authors.initials: M
authors.lastname: During
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Edith M
authors.initials: EM
authors.lastname: Gardiner
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D020738:Leptin / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D054411:Receptors, Leptin; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020738:Leptin; D009478:Neuropeptide Y; D054411:Receptors, Leptin; D017476:Receptors, Neuropeptide Y; C515447:leptin receptor, mouse; C095889:neuropeptide Y2 receptor