Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways

Baldock, PA, Sainsbury, A, Allison, S, Lin, EJD, Couzens, M, Boey, D, Enriquez, R, During, M, Herzog, H and Gardiner, EM (2005) Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways. Journal of Bone And Mineral Research, 20 10: 1851-1857. doi:10.1359/JBMR.050523


Author Baldock, PA
Sainsbury, A
Allison, S
Lin, EJD
Couzens, M
Boey, D
Enriquez, R
During, M
Herzog, H
Gardiner, EM
Title Hypothalamic control of bone formation: Distinct actions of leptin and Y2 receptor pathways
Journal name Journal of Bone And Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2005
Sub-type Article (original research)
DOI 10.1359/JBMR.050523
Volume 20
Issue 10
Start page 1851
End page 1857
Total pages 7
Editor J. A. Eisman
Place of publication USA
Publisher American Society for Bone and Mineral Research
Collection year 2005
Language eng
Subject C1
321099 Clinical Sciences not elsewhere classified
730114 Skeletal system and disorders (incl. arthritis)
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. Introduction: Central enhancement of bone formation by hypothalamic neurons is observed in leptin-deficient oblob 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. Materials and Methods: The interaction of concomitant leptin and Y2 receptor deficiency in controlling bone was examined in Y2(-/-) oblob 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 oblob, Y2(-/-), and Y2(-/-) oblob mice. However, greater bone resorption in oblob and Y2(-/-) oblob 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.
Keyword Endocrinology & Metabolism
Central Control Of Bone Formation
Y Receptor
Osteoblast
Neuropeptide Y
Hypothalamus
Leptin
Neuropeptide-y
Ob/ob Mice
Energy Homeostasis
Knockout Mice
Obese Gene
Mass
Attenuation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 07:23:20 EST