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3. Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Author

Susan J, Allison, Paul, Baldock, Amanda, Sainsbury, Ronaldo, Enriquez, Nicola J, Lee, En-Ju Deborah, Lin, Matthias, Klugmann, Matthias, Klugman, Matthew, During, John A, Eisman, Mei, Li, Lydia C, Pan, Herbert, Herzog, and Edith M, Gardiner

Subjects
Male, Aging, medicine.medical_specialty, Osteoporosis, Hypothalamus, Parathyroid hormone, Adipose tissue, White adipose tissue, Biochemistry, Bone resorption, Bone remodeling, Mice, Internal medicine, medicine, Animals, Femur, Bone Resorption, Receptor, Molecular Biology, Mice, Knockout, business.industry, Body Weight, Cell Biology, medicine.disease, Spine, Receptors, Neuropeptide Y, Endocrinology, Adipose Tissue, Female, business, Orchiectomy, Gene Deletion, Hormone
Abstract

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.

Published
2006
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6. List of Contributors

Author

Omar M.E. Albagha, Andrew Arnold, Paul Baldock, Mary L. Bouxsein, Brendan F. Boyce, Stephanie Jo Brewster, Edward M. Brown, Matthew A. Brown, David A. Bushinsky, Salin A. Chakkalakal, Roderick Clifton-Bligh, William G. Cole, Michael T. Collins, Michael R. Convente, Jessica Costa-Guda, Andria L. Culbert, Hong-Wen Deng, Olivier Devuyst, Marc K. Drezner, Emma L. Duncan, Ogo I. Egbuna, John A. Eisman, David Feldman, Mathieu Ferron, Matti Gild, Yan Guo, Kilian Guse, Ingrid A. Holm, Bryan Hudson, Takashi Igarashi, Christina Jacobsen, Harald Jüppner, Frederick S. Kaplan, Gerard Karsenty, Christopher S. Kovacs, Brendan Lee, Gabriela G. Loots, Rik J. Lories, Vitali Y. Lounev, Frank P. Luyten, Peter J. Malloy, Joan C. Marini, T. John Martin, Walter L. Miller, Orson W. Moe, Tuan V. Nguyen, Franck Oury, Christopher J. Papasian, Dhruval Patel, Bram Perdu, Siân E. Piret, M. Helen Rajpar, Stuart H Ralston, Fernando Rivadeneira, Bruce G Robinson, Merry ZC Ruan, Steven J. Scheinman, Scott J. Schurman, Yiping Shen, Eileen M. Shore, Caroline Silve, Natalie A. Sims, Anil Singh, Allen M. Spiegel, Rajesh V. Thakker, André G. Uitterlinden, Ana M. Valdes, Wim Van Hul, Lee S. Weinstein, Michael P. Whyte, Lianping Xing, Tie-Lin Yang, and Michael J. Zuscik

Published
2013
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