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J. Biol. Chem., Vol. 282, Issue 26, 19092-19102, June 29, 2007

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Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis^*

Paul A. Baldock¹, Susan J. Allison¹², Pernilla Lundberg^¶, Nicola J. Lee, Katy Slack, En-Ju D. Lin, Ronaldo F. Enriquez, Michelle M. McDonald^||, Lei Zhang, Matthew J. During^**, David G. Little^||, John A. Eisman, Edith M. Gardiner³, Ernie Yulyaningsih, Shu Lin, Amanda Sainsbury⁴, and Herbert Herzog⁴⁵

From the Bone and Mineral Program and Neuroscience Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, the ^¶Department of Oral Cell Biology, Umeå University, Umeå S-901 87, Sweden, the ^||Department of Orthopaedic Research & Biotechnology, The Children's Hospital at Westmead, Sydney 2000, Australia, the ^**Department of Molecular Medicine & Pathology, University of Auckland, Auckland 1001, New Zealand, and the Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1^-/- mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1^-/- mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

Received for publication, January 23, 2007 , and in revised form, April 19, 2007.

^* This work was supported by the National Health and Medical Research Council (NHMRC, Grant 376021 to H. H. and Grant 230820 to A. S.), by an NHMRC Fellowship (188827) and the Diabetes Australia Research Trust (to A. S.), by an NHMRC scholarship (to S. J. A.), an NHMRC Fellowship (to H. H.), by a Swedish Society for Medical Research fellowship (to P. L.), and by the Swedish Research Council for Medicine. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Present address: Laboratory of Neural Stem Cell Biology, Stem Cell Institute, University Hospital, Lund 22184, Sweden.

³ Present address: School of Medicine, University of Queensland, Brisbane 4000, Queensland, Australia.

⁴ Both authors contributed equally to this work.

⁵ To whom correspondence should be addressed: Tel.: 61-2-9295-8296; Fax: 61-2-9295-8281; E-mail: h.herzog{at}garvan.org.au.

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