RANK deletion in neuropeptide Y neurones attenuates oestrogen deficiency-related bone loss
Corresponding Author
Nicola J. Lee
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Correspondence
Nicola J. Lee and Herbert Herzog, Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Emails: [email protected]; [email protected]
Search for more papers by this authorIreni M. Clarke
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorAyse Zengin
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorRonaldo F. Enriquez
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorVanj Nagy
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Search for more papers by this authorJosef M. Penninger
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
Search for more papers by this authorPaul A. Baldock
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Herbert Herzog
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Correspondence
Nicola J. Lee and Herbert Herzog, Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Emails: [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Nicola J. Lee
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Correspondence
Nicola J. Lee and Herbert Herzog, Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Emails: [email protected]; [email protected]
Search for more papers by this authorIreni M. Clarke
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorAyse Zengin
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorRonaldo F. Enriquez
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorVanj Nagy
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Search for more papers by this authorJosef M. Penninger
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria
Search for more papers by this authorPaul A. Baldock
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Bone Biology Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Herbert Herzog
Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
St Vincents Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
Correspondence
Nicola J. Lee and Herbert Herzog, Neuroscience Division, Garvan Institute, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Emails: [email protected]; [email protected]
Search for more papers by this authorAbstract
The RANKL pathway is known to be an important aspect of the pathogenesis of oestrogen deficiency-induced bone loss. RANK deletion specifically in neuropeptide Y (NPY) neurones has been shown to enhance the ability of the skeleton to match increases in body weight caused by high-fat diet feeding, likely via the modulation of NPY levels. In the present study, we used ovariectomy in female mice to show that RANK deletion in NPY neurones attenuates bone loss caused by long-term oestrogen deficiency, particularly in the vertebral compartment. Ovariectomy led to a reduction in NPY expression levels in the arcuate nucleus of NPYcre/+;RANKlox/lox mice compared to NPYcre/+;RANKlox/+ controls. Because NPY deficient mice also displayed a similar protection against ovariectomy-induced bone loss, modulation of hypothalamic NPY signalling is the likely mechanism behind the protection from bone loss in the NPYcre/+;RANKlox/lox mice.
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REFERENCES
- 1Hanada R, Leibbrandt A, Hanada T, et al. Central control of fever and female body temperature by RANKL/RANK. Nature. 2009; 462: 505-509.
- 2Lee NJ, Clarke IM, Enriquez RF, et al. Central RANK signalling in NPY neurons alters bone mass in male mice. Neuropeptides. 2018; 68: 75-83.
- 3Baldock PA, Lee NJ, Driessler F, et al. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS ONE. 2009;4: e8415.
- 4Sasanuma H, Nakata M, Parmila K, Nakae J, Yada T. PDK1-FoxO1 pathway in AgRP neurons of arcuate nucleus promotes bone formation via GHRH-GH-IGF1 axis. Mol Metab. 2017; 6: 428-439.
- 5Lee NJ, Herzog H. NPY regulation of bone remodelling. Neuropeptides. 2009; 43: 457-463.
- 6Wong IP, Driessler F, Khor EC, et al. Peptide YY regulates bone remodeling in mice: a link between gut and skeletal biology. PLoS ONE. 2012; 7: e40038.
- 7Baldock PA, Lin S, Zhang L, et al. Neuropeptide y attenuates stress-induced bone loss through suppression of noradrenaline circuits. J Bone Miner Res. 2014;29: 2238-2249.
- 8Nguyen AD, Lee NJ, Wee NKY, et al. Uncoupling protein-1 is protective of bone mass under mild cold stress conditions. Bone. 2018; 106: 167-178.
- 9Lee NJ, Nguyen AD, Enriquez RF, et al. NPY signalling in early osteoblasts controls glucose homeostasis. Mol Metab. 2015; 4: 164-174.
- 10Escobar CM, Krajewski SJ, Sandoval-Guzman T, Voytko ML, Rance NE. Neuropeptide Y gene expression is increased in the hypothalamus of older women. J Clin Endocrinol Metab. 2004;89: 2338-2343.
- 11Ainslie DA, Morris MJ, Wittert G, Turnbull H, Proietto J, Thorburn AW. Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y. Int J Obes Relat Metab Disord. 2001;25: 1680-1688.
- 12Clegg DJ, Brown LM, Zigman JM, et al. Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats. Diabetes. 2007;56: 1051-1058.
- 13Shimizu H, Ohtani K, Kato Y, Tanaka Y, Mori M. Withdrawal of [corrected] estrogen increases hypothalamic neuropeptide Y (NPY) mRNA expression in ovariectomized obese rat. Neurosci Lett. 1996;204: 81-84.
- 14Zengin A, Nguyen AD, Wong IP, et al. Neuropeptide Y mediates the short-term hypometabolic effect of estrogen deficiency in mice. Int J Obes (Lond). 2013; 37: 390-398.
- 15Karl T, Duffy L, Herzog H. Behavioural profile of a new mouse model for NPY deficiency. Eur J Neurosci. 2008; 28: 173-180.
- 16Shi YC, Lau J, Lin Z, et al. Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN. Cell Metab. 2013;17: 236-248.
- 17Sainsbury A, Schwarzer C, Couzens M, et al. Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice. Proc Natl Acad Sci USA. 2002;99: 8938-8943.
- 18Baldock PA, Sainsbury A, Couzens M, et al. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest. 2002;109: 915-921.
- 19Qi Y, Fu M, Herzog H. Y2 receptor signalling in NPY neurons controls bone formation and fasting induced feeding but not spontaneous feeding. Neuropeptides. 2016; 55: 91-97.
- 20Baldock PA, Allison SJ, Lundberg P, et al. Novel role of Y1 receptors in the coordinated regulation of bone and energy homeostasis. J Biol Chem. 2007;282: 19092-19102.
- 21Lee NJ, Doyle KL, Sainsbury A, et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J Bone Miner Res. 2010;25: 1736-1747.
- 22Lee NJ, Nguyen AD, Enriquez RF, et al. Osteoblast specific Y1 receptor deletion enhances bone mass. Bone. 2011;48: 461-467.
- 23Sousa DM, Baldock PA, Enriquez RF, et al. Neuropeptide Y Y1 receptor antagonism increases bone mass in mice. Bone. 2012;51: 8-16.
- 24Lee NJ, Allison S, Enriquez RF, Sainsbury A, Herzog H, Baldock PA. Y2 and Y4 receptor signalling attenuates the skeletal response of central NPY. J Mol Neurosci. 2011;43: 123-131.
- 25Allison SJ, Baldock PA, Enriquez RF, et al. Critical interplay between neuropeptide Y and sex steroid pathways in bone and adipose tissue homeostasis. J Bone Miner Res. 2009;24: 294-304.
- 26Allison SJ, Baldock P, Sainsbury A, et al. Conditional deletion of hypothalamic Y2 receptors reverts gonadectomy-induced bone loss in adult mice. J Biol Chem. 2006;281: 23436-23444.
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