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J. Biol. Chem., Vol. 281, Issue 33, 23436-23444, August 18, 2006

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Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice^*

Susan J. Allison, Paul Baldock, Amanda Sainsbury, Ronaldo Enriquez, Nicola J. Lee, En-Ju Deborah Lin, Matthias Klugman^¶, Matthew During^¶, John A. Eisman, Mei Li^||, Lydia C. Pan^||, Herbert Herzog¹², and Edith M. Gardiner^**1

From the Bone and Mineral Research Program and Neuroscience Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia, the ^¶Department of Molecular Medicine and Pathology, University of Auckland, 85 Park Road, Grafton, Auckland, New Zealand, ^**University of Queensland School of Medicine, Princess Alexandra Hospital, Ipswich Road, Brisbane, Queensland 4120, Australia, and ^||Pfizer Global Research and Development, Inc., Groton, Connecticut 06340

Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormone-deficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.

Received for publication, May 19, 2006

^* This work was supported by Pfizer Inc., National Health and Medical Research Council Project Grant 276412, a National Health and Medical Research Council scholarship (to S. J. A.), and National Health and Medical Research Council fellowships (to A. S. and H. H.). 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 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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