Cited by 1,311Bone Metabolism and DiseasesBone health and osteoporosis researchRegulation of Appetite and Obesity

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Leptin regulation of bone resorption by the sympathetic nervous system and CART

Elefteriou, Florent, Ahn, Jong Deok, Takeda, Shu, Starbuck, Michael, Yang, Xiangli, Liu, Xiuyun, Kondo, Hisataka, Richards, William G., Bannon, Tony W., Noda, Masaki, Clement, Karine, Vaisse, Christian, Karsenty, Gerard·2005·Nature

DOI 10.1038/nature03398

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Abstract

Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase…

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Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
Lacey, D. L., Timms, E., Tan, H.-L., Kelley, M. J., Dunstan, C. R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81569-x · Cited by 5,439
Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81865-6 · Cited by 3,030
Leptin Inhibits Bone Formation through a Hypothalamic Relay
Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A. F., Beil, F. T., Shen, J., Vinson, C., Rueger, J. M., & Karsenty, G. (2000) · Cell · doi:10.1016/s0092-8674(00)81558-5 · Cited by 2,077
Self-citation
Leptin Regulates Bone Formation via the Sympathetic Nervous System
Takeda, S., Elefteriou, F., Levasseur, R., Liu, X., Zhao, L., Parker, K. L., Armstrong, D., Ducy, P., & Karsenty, G. (2002) · Cell · doi:10.1016/s0092-8674(02)01049-8 · Cited by 1,735
Self-citation
Genetic regulation of osteoclast development and function
Teitelbaum, S. L., & Ross, F. P. (2003) · Nature Reviews Genetics · doi:10.1038/nrg1122 · Cited by 1,720
Hypothalamic CART is a new anorectic peptide regulated by leptin
Kristensen, P. L., Judge, M. E., Thim, L., Ribel, U., Christjansen, K. N., Wulff, B. S., Clausen, J. T., Jensen, P. B., Madsen, O. D., Vrang, N., et al. (1998) · Nature · doi:10.1038/29993 · Cited by 1,282
OSTEOBLASTIC CELLS ARE INVOLVED IN OSTEOCLAST FORMATION
Takahashi, N., Akatsu, T., Udagawa, N., Sasaki, T., Yamaguchi, A., Moseley, J. M., Martin, T. J., & Suda, T. (1988) · Endocrinology · doi:10.1210/endo-123-5-2600 · Cited by 934
ATF4 Is a Substrate of RSK2 and an Essential Regulator of Osteoblast Biology
Yang, X., Matsuda, K., Bialek, P., Jacquot, S., Masuoka, H. C., Schinke, T., Li, L., Brancorsini, S., Sassone‐Corsi, P., Townes, T. M., et al. (2004) · Cell · doi:10.1016/s0092-8674(04)00344-7 · Cited by 822
Self-citation
Two Distinct Osteoblast-Specific cis-Acting Elements Control Expression of a Mouse Osteocalcin Gene
Ducy, P. F., & Karsenty, G. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.4.1858 · Cited by 570
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Leptin Receptors and β2-Adrenergic Receptor mRNA Expression in Brain Injury-Related Heterotopic Ossification
Chauveau, C., Devedjian, J.-C., Delecourt, C., Jeanfils, J., Hardouin, P., & Broux, O. (2008) · Journal of Receptors and Signal Transduction · doi:10.1080/10799890802239762 · Cited by 17
“Then the neurotransmitter noradrenalin activates β2-adrenergic receptors β2AR) on osteoblasts leading to inhibition of bone formation and increase in bone resorption via RANK ligand production (8).”
Background
Gut microbiota and bone aging: Focusing on the gut-X axis modes
Zhang, Y.-W., Li, R.-Y., Wu, Y., Wang, P., Zhou, Q., & Su, J. (2026) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2026.101064 · Cited by 17
“…to leptin receptors expressed in brainstem neurons, leptin inhibits the release of serotonin in brainstem neurons and the expression of serotonin receptor 2C in the ventromedial nucleus of hypothalamus, and promotes bone resorption via β 2-adrenergic receptors expressed in osteoblasts [125].”
Social Isolation Causes Cortical and Trabecular Bone Loss in Adult Male, but not Female, C57BL/6J Mice
Mountain, R. V., Langlais, A. L., Hu, D. Z., Baron, R., Lary, C. W., & Motyl, K. J. (2023) · Bone · doi:10.1016/j.bone.2023.116762 · Cited by 16
Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density
Veldhuis‐Vlug, A. G., Oei, L., Souverein, P. C., Tanck, M. W. T., Rivadeneira, F., Zillikens, M. C., Kamphuisen, P. W., der Zee, A. H. M., de Groot, M., Albert Hofman, D., et al. (2015) · Osteoporosis International · doi:10.1007/s00198-015-3087-0 · Cited by 16
“B2AR knockout mice have an increased bone mass and treat-ment with beta-blockers or beta-agonists increases and decreases bone mass respectively [1, 33 – 36].”
A collaboration investigating endocannabinoid signalling in brain and bone
Zimmer, A. (2016) · Journal of Basic and Clinical Physiology and Pharmacology · doi:10.1515/jbcpp-2015-0125 · Cited by 16
“These fibres release norepinephrine, which restrains bone formation and stimulates bone resorption [32, 33], through a mechanism involving the activation of β2-adrenergic receptors on osteoblasts.”
Background
Probing the response of human osteoblasts following exposure to sympathetic neuron‐like PC‐12 cells in a 3D coculture model
Erndt‐Marino, J. D., & Hahn, M. S. (2016) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.35964 · Cited by 17
An Old Friend in a New Light: The Role of Osteocalcin in Energy Metabolism
Sullivan, T. R., Duque, G., KEECH, A. C., & Herrmann, M. (2011) · Cardiovascular Therapeutics · doi:10.1111/j.1755-5922.2011.00300.x · Cited by 17
Energy expenditure and bone formation share a common sensitivity to AP-1 transcription in the hypothalamus
Rowe, G. C., Vialou, V., Sato, K., Saito, H., Yin, M., Green, T. A., Lotinun, S., Kveiborg, M., Horne, W. C., Nestler, E. J., et al. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1618 · Cited by 18
Inducible Models of Bone Loss
Doucette, C. R., & Rosen, C. J. (2014) · Current Protocols in Mouse Biology · doi:10.1002/9780470942390.mo140071 · Cited by 16
Serum leptin concentration, bone mineral density and bone biochemical markers in a sample of Egyptian women: A possible relationship
Ibrahim, S. E., Fawzy, H. M., Helmy, A., Galal, Z. A., & Salam, M. H. A. (2011) · The Egyptian Rheumatologist · doi:10.1016/j.ejr.2011.07.001 · Cited by 16
FIAT represses bone matrix mineralization by interacting with ATF4 through its second leucine zipper
Yu, V. W. C., Gauthier, C., & St‐Arnaud, R. (2008) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21881 · Cited by 16
“…of residue serine 254 by protein kinase A (PKA) [Elefteriou et al., 2005], ATF4 also induces the expression of receptor activator of nuclear factor kB ligand (RANKL) on the surface of osteoblasts, which serves as a potent stimulator for osteoclast differentiation [Elefteriou et al., 2005].”
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Adipokine Effects on Bone
Reid, I. R., & Richards, J. B. (2009) · Clinical Reviews in Bone and Mineral Metabolism · doi:10.1007/s12018-009-9048-4 · Cited by 16
“The Karsenty group have dramatically changed views of the regulation of bone biology with an elegant series of papers showing that infusion of leptin into the third ventricle causes bone loss in leptin-deficient and wild-type mice through inhibition of bone formation [3] and stimulation of bone resorption [ 13 ].”
Background
CNS Targets of Adipokines
Beall, C., Hanna, L., & Ellacott, K. L. J. (2017) · Comprehensive physiology · doi:10.1002/cphy.c160045 · Cited by 16
Roles of osteoclasts in pathological conditions
Kitazawa, S., Haraguchi, R., & Kitazawa, R. (2024) · Pathology International · doi:10.1111/pin.13500 · Cited by 15
“40 Given the high expression of ATF4 in bone, this ATF4 ‐ mediated regulatory system is likely to play a signi ﬁ cant role in osteoblast ‐ speci ﬁ c RANKL expression.”
Hypertension promotes bone loss and fragility by favoring bone resorption in mouse models
Hennen, E. M., Uppuganti, S., de la Visitación, N., Chen, W., Krishnan, J., Vecchi, L. A., Patrick, D. M., Siedliński, M., Lemoli, M., Delgado, R., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci184325 · Cited by 15
“As examples, increased sympathetic tone has been shown to promote bone loss (44), and oxidative injury promotes osteoclast formation (45).”
Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study
Oehler, N., Rolvien, T., Schmidt, T., Butscheidt, S., Oheim, R., Barvencik, F., & Mussawy, H. (2018) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-018-0976-2 · Cited by 15
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Morris, A. J., Parker, R. S., Nazzal, M. K., Natoli, R. M., Fehrenbacher, J. C., Kacena, M. A., & White, F. A. (2024) · Current Osteoporosis Reports · doi:10.1007/s11914-023-00846-y · Cited by 15
“The influence of the nervous system persists, primarily through its regulation of osteoclast activity and, thereby, bone resorption [26–28].”
Background
Mechanical Unloading Promotes Osteoclastic Differentiation and Bone Resorption by Modulating the MSC Secretome to Favor Inflammation
Wang, W., Zheng, X., Wang, H., Zuo, B., Chen, S., & Li, J. (2024) · Cell Transplantation · doi:10.1177/09636897241236584 · Cited by 15
“Many external factors, such as hormone levels 5 , neural signals 6 , and mechanical signals 7–10 regulate the coupling process.”
Background
Introduction to Bone Development, Remodelling and Repair
Gruber, R., Pietschmann, P., & Peterlik, M. (2008) · Medical radiology · doi:10.1007/978-3-540-68604-0_1 · Cited by 16
Chronic stress, sympathetic activation and skeletal metastasis of breast cancer cells
Elefteriou, F. (2015) · BoneKEy Reports · doi:10.1038/bonekey.2015.61 · Cited by 15
“Accordingly, mutant mice lacking the b2AR display a late-onset increase in bone mass caused by high bone formation and low bone resorption.(28,29) Adrenergic agonists promote osteoclastogenesis via action on osteoblasts and stimulation of Rankl (Receptor Activator of Nuclear Factor Kappa-B Ligand) expression.”
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Goto, S., Fujii, H., Kono, K., Nakai, K., Hamada, Y., Yamato, H., Shinohara, M., Kitazawa, R., Kitazawa, S., Nishi, S., et al. (2011) · American Journal of Nephrology · doi:10.1159/000330853 · Cited by 15
Successful Application of a Galanin-Coated Scaffold for Periodontal Regeneration
Ma, W., Lyu, H., Pandya, M., Gopinathan, G., Luan, X., & Diekwisch, T. G. H. (2021) · Journal of Dental Research · doi:10.1177/00220345211028852 · Cited by 15
Guanabenz inhibits alveolar bone resorption in a rat model of periodontitis
Muramatsu, R., Sato, T., Hamamura, K., Miyazawa, K., Takeguchi, A., Tabuchi, M., Togari, A., & Goto, S. (2021) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2021.08.003 · Cited by 15
Physiologie du tissu osseux
Thomas, T., Martin, A., & Lafage‐Proust, M. (2008) · EMC - Appareil locomoteur · doi:10.1016/s0246-0521(08)40315-7 · Cited by 24
Leptin-based therapeutics
Scolaro, L. M., Cassone, M., Kolaczynski, J. W., Ötvös, L., & Surmacz, E. (2010) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.10.61 · Cited by 15
Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts
Finkelshtein, E., Lotinun, S., Levy-Apter, E., Arman, E., den Hertog, J., Baron, R., & Elson, A. (2014) · Molecular Biology of the Cell · doi:10.1091/mbc.e14-03-0788 · Cited by 15
Sympathetic Regulation of Tertiary Dentinogenesis via Beta-2 Adrenergic Receptor on Rat Odontoblasts
Gu, J., Ikeda, H., & Suda, H. (2015) · Journal of Endodontics · doi:10.1016/j.joen.2015.01.010 · Cited by 15
Novel Targets and Therapeutics for Bone Loss
Margolis, R., & Wimalawansa, S. J. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1346.040 · Cited by 15
Isoproterenol Increases RANKL Expression in a ATF4/NFATc1-Dependent Manner in Mouse Osteoblastic Cells
Baek, K., Park, H.-J., Baek, J., & Kim, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102204 · Cited by 15
“decreases osteoblast proliferation [2] and stimulates bone resorption by increasing receptor activator of NF-κB ligand (RANKL) expression [3].”
BackgroundInfluential
The Expanding Life and Functions of Osteogenic Cells: From Simple Bone-Making Cells to Multifunctional Cells and Beyond
Marie, P. J., & Cohen-Solal, M. E. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3356 · Cited by 15
“One mediator linking leptin signaling in the brain to bone remodeling is the sympathetic tone, which inhibits bone formation through b2 adrenergic receptors (Adrb2) expressed in osteoblasts.((198,199)) This does not necessarily exclude the possibility that leptin can affect bone directly, although there have been conf…”
Background
Novel leptin receptor signaling mutants identify location and sex‐dependent modulation of bone density, adiposity, and growth
McCabe, I. C., Fedorko, A., Myers, M. G., Leinninger, G. M., Scheller, E. L., & McCabe, L. R. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.27726 · Cited by 15
Combinatorial control of ATF4‐dependent gene transcription in osteoblasts
St‐Arnaud, R., & Hekmatnejad, B. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06197.x · Cited by 15
Bone metabolism and energy balance: role for leptin
Thomas, T., & Martin, A. (2005) · Joint Bone Spine · doi:10.1016/j.jbspin.2005.10.005 · Cited by 15
FIAT is co-expressed with its dimerization target ATF4 in early osteoblasts, but not in osteocytes
Yu, V. W. C., Akhouayri, O., & St‐Arnaud, R. (2009) · Gene Expression Patterns · doi:10.1016/j.gep.2009.02.002 · Cited by 15
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“Global knockout of CART decreased bone mass, mainly through upregulating osteoclast activity [133].”
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Isojima, T., Walker, E. C., Poulton, I. J., McGregor, N. E., Wicks, I. P., Gooi, J. H., Martin, T. J., & Sims, N. A. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4654 · Cited by 14
“Whether these cytokines influence skeletal structure through the sympathetic nervous system is not known, but other factors, including leptin, regulate both bone formation and resorption through this pathway,((66,67)) suggesting this possibility.”
Background
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“This action is mainly mediated by beta-2 adrenergic receptor expressed by osteoblasts [31, 32].”
Background
Skeletal integration of energy homeostasis: Translational implications
Lecka‐Czernik, B., & Rosen, C. J. (2015) · Bone · doi:10.1016/j.bone.2015.07.026 · Cited by 14
β₂Adrenergic Receptor Activation Suppresses Bone Morphogenetic Protein (BMP)‐Induced Alkaline Phosphatase Expression in Osteoblast‐Like MC3T3E1 Cells
Yamada, T., Ezura, Y., Hayata, T., Moriya, S., Shirakawa, J., Notomi, T., Arayal, S., Kawasaki, M., Izu, Y., Harada, K., et al. (2014) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25071 · Cited by 14
“Sympathetic tone regulates both bone formation and bone resorption locally as well as centrally [Elefteriou et al., 2005; Nagao et al., 2011; Bajayo et al., 2012; D0Amelio et al., 2012].”
BackgroundSelf-citation
Bone metabolism and adipokines: are there perspectives for bone diseases drug discovery?
Scotece, M., Conde, J., Abella, V., López, V., Pino, J., Lago, F., Gómez-Reino, J. J., & Gualillo, O. (2014) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2014.922539 · Cited by 14
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Background
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Su, J., Xie, Q., Liu, W.-J., Lai, P., Liu, D., Tang, L.-H., Dong, T. T.-X., Su, Z., Tsim, K. W. K., Lai, X., et al. (2013) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2013/747240 · Cited by 14
“…hormonal dysregulation resulting from the sharp decline of ovarian supply of germ cells and the dramatic endocrine function change [4], physicians have introduced hormone replacement therapy (HRT) as the prevailing therapeutic regime to allay series of perimenopausal symptoms 30 years ago [5].”
Background
Correlation between adiponectin, leptin, insulin growth factor-1 and bone mineral density in pre and postmenopausal women.
Corina, M., Vulpoi, C., & Brǎnişteanu, D. D. D. (2012) · PubMed · Cited by 14
Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice
Le, P. T., Bishop, K. A., Maridas, D. E., Motyl, K. J., Brooks, D. J., Nagano, K., Baron, R., Bouxsein, M., & Rosen, C. J. (2017) · Bone · doi:10.1016/j.bone.2017.08.006 · Cited by 14
“The SNS has emerged as a major regulator of bone metabolism with activation of the β2AR on osteoblasts as a primary SNS target leading to an increase in Rankl expression and increased osteoclastogenesis/bone resorption causing lower bone mass [20, 22, 42].”
Background
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Background
Stress management in obesity during a thermal spa residential programme (ObesiStress): protocol for a randomised controlled trial study
Dutheil, F., Chaplais, E., Vilmant, A., Courteix, D., Duché, P., Abergel, A., Pfabigan, D. M., Han, S., Mobdillon, L., Vallet, G. T., et al. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-027058 · Cited by 14
Hematopoietic Stem Cell Mobilization: Current Collection Approaches, Stem Cell Heterogeneity, and a Proposed New Method for Stem Cell Transplant Conditioning
Menendez-Gonzalez, J. B., & Hoggatt, J. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10272-1 · Cited by 13
A high activity index of stearoyl-CoA desaturase is associated with increased risk of fracture in men
Melhus, H., Risérus, U., Warensjö, E., Wernroth, L., Jensevik, K., Berglund, L., Vessby, B., & Michaëlsson, K. (2007) · Osteoporosis International · doi:10.1007/s00198-007-0521-y · Cited by 14
“, the dominant regulator of adipogenesis, inhibits osteoblast differentiation [2], and that leptin, an anorexigenic metabolic hormone that is secreted in proportion to fat mass, is a regulator of both bone formation and resorption [3–5].”
Propranolol, a β-adrenergic antagonist, attenuates the decrease in trabecular bone mass in high calorie diet fed growing mice
Baek, K., Hwang, H. R., Park, H.-J., Kwon, A., Qadir, A. S., & Baek, J. (2014) · BMB Reports · doi:10.5483/bmbrep.2014.47.9.265 · Cited by 14
“proliferation (9), and by stimulating bone resorption (10).”
Background
Metabolic regulation by protein tyrosine phosphatases
Knobler, H., & Elson, A. (2014) · Journal of Biomedical Research · doi:10.7555/jbr.28.20140012 · Cited by 14
“and fertility [30-32] ; these will not be discussed here.”
Background
RANKL Reduces Body Weight and Food Intake via the Modulation of Hypothalamic NPY/CART Expression
Zhu, P., Zhang, Z., Huang, X., Liang, S., Khandekar, N., Song, Z.-Y., & Lin, S. (2018) · International Journal of Medical Sciences · doi:10.7150/ijms.24373 · Cited by 14
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Background
Altered bone microarchitecture in a type 1 diabetes mouse model Ins2Akita
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BackgroundResultInfluential
ΔFosB Requires Galanin, but not Leptin, to Increase Bone Mass via the Hypothalamus, but both are needed to increase Energy expenditure
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“Indeed, a collection of published data gave impetus to the idea that changes in energy regulation, and consequently glucose metabolism, can influence bone homeostasis((25,61,71)) and reciprocally that bone remodeling can affect energy and glucose metabolism.”
Novel factors as therapeutic targets to treat diabetes. Focus on leptin and ghrelin
Gómez, R., Lago, F., Gómez-Reino, J. J., & Gualillo, O. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220902914834 · Cited by 14
“Targets (2009) 13(5) Leptin also has peripheral effects on liver, skeletal muscle, pancreas, bones and several other tissues [17-20].”
Background
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Beil, F. T., Seitz, S. A., Priemel, M., Barvencik, F., von Domarus, C., Rueger, J. M., Amling, M., & Pogoda, P. (2008) · European Journal of Trauma and Emergency Surgery · doi:10.1007/s00068-008-8201-y · Cited by 14
“The fact that the central control of bone mass is a regularization mechanism of general biological meaning was shown by proving the leptin-dependent control of bone formation in sheep [58].”
Interaction between exercise, dietary restriction and age-related bone loss in a rodent model of male senile osteoporosis
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Osteoporosis under psychological stress: mechanisms and therapeutics
Xu, H., Liu, J.-X., Zhou, Z.-K., Zheng, C., Sui, B., Yuan, Y., Kong, L., Jin, Y. J., & Chen, J. (2024) · Life Medicine · doi:10.1093/lifemedi/lnae009 · Cited by 13
Effect of the supplementation of exogenous complex non-starch polysaccharidases on the growth performance, rumen fermentation and microflora of fattening sheep
Xue, Y., Sun, H., Guo, H., Nie, C., Nan, S., Lu, Q., Chen, C., & Zhang, W. (2024) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1396993 · Cited by 13
An atlas of brain-bone sympathetic neural circuits in mice
Ryu, V., Gumerova, A. A., Witztum, R., Korkmaz, F., Cullen, L., Kannangara, H. S., Moldavski, O., Barak, O., Lizneva, D., Goosens, K. A., et al. (2024) · eLife · doi:10.7554/elife.95727 · Cited by 13
“Elegant studies have suggested that increased sympathetic nervous system (SNS) tone causes bone loss through a reduction in bone formation, which is coupled with increased bone resorption (Elefteriou, 2018; Elefteriou et al , 2005; Takeda et al , 2002).”
Functional characterization of the promoter of human kinetochore protein HEC1: Novel link between regulation of the cell cycle protein and CREB family transcription factors
Cheng, L., Li, L., Qiao, X., Liu, J. L., & Yao, X. (2007) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/j.bbaexp.2007.07.005 · Cited by 13
Decreased TNF-α gene expression in periodontal ligature in MSG-obese rats: A possible protective effect of hypothalamic obesity against periodontal disease?
Brandelero, S., Bonfleur, M. L., Ribeiro, R. A., Vanzela, E. C., Nassar, C. A., Nassar, P. O., & Balbo, S. L. (2011) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2011.08.024 · Cited by 13
Elcatonin injections suppress systemic bone resorption without affecting cortical bone regeneration after drill‐hole injuries in mice
Katae, Y., Tanaka, S., Sakai, A., Nagashima, M., Hirasawa, H., & Nakamura, T. (2009) · Journal of Orthopaedic Research® · doi:10.1002/jor.20920 · Cited by 13
Stimulating angiogenesis mitigates the unloading-induced reduction in osteogenesis in early-stage bone repair in rats
Matsumoto, T., & Sato, S. (2015) · Physiological Reports · doi:10.14814/phy2.12335 · Cited by 13
A selective membrane estrogen receptor agonist maintains autonomic functions in hypoestrogenic states
Kelly, M. J., & Rønnekleiv, O. (2013) · Brain Research · doi:10.1016/j.brainres.2013.03.020 · Cited by 13
“In fact, there is an increase in bone formation and a decrease in bone reabsorption in adrenergic β2 receptor knockout mice (Elefteriou et al., 2005).”
Background
Genes and Molecular Pathways of the Osteogenic Process
Lattanzi, W., & Bernardini, C. (2012) · InTech eBooks · doi:10.5772/34022 · Cited by 15
Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts
Hirai, T. (2017) · Neurochemical Research · doi:10.1007/s11064-017-2365-y · Cited by 14
Association between renin–angiotensin–aldosterone system blockade and future osteoporotic fracture risk in hypertensive population
Chen, C.-I., Yeh, J., Tsao, N.-W., Lin, F.-Y., Shih, C., Chiang, K., Kao, Y., Fang, Y.-A., Tsai, L.-W., Liu, W.-C., et al. (2017) · Medicine · doi:10.1097/md.0000000000008331 · Cited by 13
Suppression of tooth movement‐induced sclerostin expression using β‐adrenergic receptor blockers
Uchibori, S., Sekiya, T., Sato, T., Hayashi, K., Takeguchi, A., Muramatsu, R., Ishizuka, K., Kondo, H., Miyazawa, K., Togari, A., et al. (2020) · Oral Diseases · doi:10.1111/odi.13280 · Cited by 16
Self-citation
Clinical, Cellular and Molecular Phenotypes of Aging Bone
Syed, F. A., Iqbal, J. Z., Peng, Y., Sun, L., & Zaidi, M. (2010) · Interdisciplinary topics in gerontology and geriatrics · doi:10.1159/000320001 · Cited by 13
The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer
Brennan, D. J., O’Connor, D. P., Laursen, H., McGee, S. F., McCarthy, S., Zagożdżon, R., Rexhepaj, E., Culhane, A. C., Martin, F., Duffy, M. J., et al. (2011) · Oncogene · doi:10.1038/onc.2011.519 · Cited by 13
“…a variety of physiological and pathological processes, including regulation of body mass (Rogge et al., 2008), inhibition of food intake (Arora and Anubhuti, 2006), energy homeostasis (Koylu et al., 2006), bone metabolism (Elefteriou et al., 2005) and neuroendocrine malignancy (Bech et al., 2008).”
Influential
Relationship between age-related reference values of serum osteoprotegerin and leptin in native Chinese women and compared with those in women of other races
Wu, X., Wu, X., Xie, H., Zhang, H., Luo, X., Liu, S., Peng, Y., Dai, R.-C., & Liao, E.-Y. (2007) · Clinica Chimica Acta · doi:10.1016/j.cca.2007.11.024 · Cited by 13
ICV vs. VMH injection of leptin: Comparative effects on hypothalamic gene expression
Ambati, S., Duan, J., Choi, Y., Hartzell, D. L., Della‐Fera, M. A., & Baile, C. A. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.09.014 · Cited by 13
Autonomic Nervous System in Bone Remodeling: From Mechanisms to Novel Therapies in Orthopedic Diseases
Xia, R., Peng, H., Zhu, X., Suolang, W., Pambayi, S. T. L., Yang, X., Zeng, Y., & Shen, B. (2025) · Orthopaedic Surgery · doi:10.1111/os.70010 · Cited by 12
“Leptin has been shown to modulate bone homeostasis through the SNS [27, 33, 34], with leptin stimulating the hypothalamus to increase sympathetic outflow, which involves the activation of various neurotransmitters such as serotonin and NE.”
Self-citation
Brain–Bone Axis in Physiological and Pathological Conditions
Massaccesi, L., Romanelli, M. M. C., & Galliera, E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199822 · Cited by 13
“These effects are mediated by neural circuits that transmit signals to bone cells through the sympathetic nervous system [74].”
Genetic variants in obesity-related genes and the risk of osteoporotic fracture. The Hortega Follow-up Study
Usategui‐Martín, R., Pérez‐Castrillón, J. L., Briongos-Figuero, L. S., Otero, J. A., Lara-Hernández, F., García-Sorribes, S., Martín‐Vallejo, J., García-García, A.-B., Chaves, F. J., & Martı́n-Escudero, J. C. (2022) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2701032 · Cited by 11
“There is a common central regulation of bone metabolism and metabolic fate through the hypothalamus and sympathetic nervous system [13,19,20].”
Background
Implications of circadian disruption on intervertebral disc degeneration: The mediating role of sympathetic nervous system
Song, Z., Yan, M., Zhang, S., Hu, B., Qing, X., Shao, Z., Chen, S., Lv, X., & Liu, H. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102633 · Cited by 12
Accelerated fracture healing accompanied with traumatic brain injury: A review of clinical studies, animal models and potential mechanisms
Jin, Z., Chen, Z., Liang, T., Liu, W., Shan, Z., Tan, D., Chen, J., Hu, J. X., Qin, L., & Xu, J. (2025) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2024.10.008 · Cited by 12
Targeting skeletal interoception: a novel mechanistic insight into intervertebral disc degeneration and pain management
Zhu, H., Ren, J. Z., Wang, X., Qin, W., & Xie, Y. (2025) · Journal of Orthopaedic Surgery and Research · doi:10.1186/s13018-025-05577-7 · Cited by 13
“Binding of NE to β2-AR on OBs inhibits their proliferation and differentiation, whereas binding to α2-AR increases the expression of RANKL, thereby promoting bone resorption [133].”
Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications
Gold, P. W., Pavlatou, M. G., Michelson, D., Mouro, C. M., Kling, M. A., Wong, M., Licinio, J., & Goldstein, S. A. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.38 · Cited by 12
Serotonin
Yadav, V. K. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-415784-2.00005-1 · Cited by 12
Regulation of Granulosa Cell Cocaine and Amphetamine Regulated Transcript (CART) Binding and Effect of CART Signaling Inhibitor on Granulosa Cell Estradiol Production During Dominant Follicle Selection in Cattle1
Folger, J. K., Jimenez‐Krassel, F., Ireland, J. J., Lv, L., & Smith, G. W. (2013) · Biology of Reproduction · doi:10.1095/biolreprod.113.111609 · Cited by 12
“Cartpt mutant mice display indices of osteoporosis [45], whereas female transgenic mice overexpressing Cartpt display an increase in bone mass [46].”
Background
Targeting the integrated stress response in ophthalmology
Chu, H.-S., Peterson, C., Jun, A. S., & Foster, J. W. (2021) · Current Eye Research · doi:10.1080/02713683.2020.1867748 · Cited by 12
“kinase (RSK2) and protein kinase A (PKA) are two kinases that phosphorylate ATF4 and enhance its transcriptional activity.(154,155) Reversible RSK2 inhibitors SL0101 and BI-”
Background
Oxytocin Involvement in Body Composition Unveils the True Identity of Oxytocin
Camerino, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126383 · Cited by 13
Neural regulation of alveolar bone remodeling and periodontal ligament metabolism during orthodontic tooth movement in response to therapeutic loading
Zhang, M., Yu, Y., He, D., Liu, D., & Zhou, Y. (2022) · Journal of the World Federation of Orthodontists · doi:10.1016/j.ejwf.2022.08.003 · Cited by 12
Structure of the Complex between Phosphorylated Substrates and the SCF β-TrCP Ubiquitin Ligase Receptor: A Combined NMR, Molecular Modeling, and Docking Approach
Evrard‐Todeschi, N., Pons, J., Gharbi‐Benarous, J., Bertho, G., Bénarous, R., & Girault, J. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci800248u · Cited by 12
Differential effects of adiponectin in osteoblast-like cells
Pacheco-Pantoja, E. L., Fraser, W. D., Wilson, P. J. M., & Gallagher, J. A. (2014) · Journal of Receptors and Signal Transduction · doi:10.3109/10799893.2014.898658 · Cited by 12
“of plasma leptin than non-obese premenopausal women (11), and leptin regulates processes of bone remodelling (12).”
Background
Effects of Chronic Estrogen Administration in the Ventromedial Nucleus of the Hypothalamus (VMH) on Fat and Bone Metabolism in Ovariectomized Rats
Zhang, Z., Liu, J., Veldhuis‐Vlug, A. G., Su, Y. R., Foppen, E., van der Eerden, B. C. J., Koedam, M., Bravenboer, N., Kalsbeek, A., Boelen, A., et al. (2016) · Endocrinology · doi:10.1210/en.2016-1481 · Cited by 12
Intermittent hypoxia causes mandibular growth retardation and macroglossia in growing rats
Hosomichi, J., Kuma, Y., Oishi, S., Nagai, H., Maeda, H., Usumi‐Fujita, R., Shimizu, Y., Kaneko, S., Shitano, C., Suzuki, J., et al. (2017) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/j.ajodo.2016.02.033 · Cited by 12
“Metabolic factors play significant roles in the mechanisms controlling the association of body weight and fat mass with bone mass.(33) In fact, body weight is a significant predictor of bone mass in growth.”
Background
Heart Rate and Bone Mineral Density in Older Women with Hypertension: Results from the Korea National Health and Nutritional Examination Survey
Jung, M., Youn, H., Ihm, S., Jung, H. O., & Hong, K.-S. (2018) · Journal of the American Geriatrics Society · doi:10.1111/jgs.15359 · Cited by 12
“Under the control of the hypothalamus, the sympathetic nervous system affects osteoblasts through beta 2-adrenergic receptors, and increased sympathetic tone results in greater bone resorption and less bone formation.(9) The autonomic nervous system is also important for maintaining cardiovascular function,(12) althou…”
Background
Maternal vitamin B12 in mice positively regulates bone, but not muscle mass and strength in post-weaning and mature offspring
Singh, P. P., Telnova, S., Zhou, B., Mohamed, A. D., Mello, V. D., Wackerhage, H., Guo, X.-D. E., Panda, A. K., & Yadav, V. K. (2021) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00355.2020 · Cited by 13
The sympathies of the body: functional organization and neuronal differentiation in the peripheral sympathetic nervous system
Ernsberger, U., Deller, T., & Rohrer, H. (2021) · Cell and Tissue Research · doi:10.1007/s00441-021-03548-y · Cited by 12
“A critical finding was the demonstration that among the two phases of bone remodeling, bone resorption, and bone formation, the former is favored by sympathetic nervous activity due to promoting an osteoclast differentiation pathway through noradrenergic transmission (Elefteriou et al. 2005).”
Background
The relationship between the levels of gonadotropic hormones and OPG, leptin, TGF-β1 and TGF-β2 in Chinese adult women
Wu, X., Wu, X.-P., Luo, X., Xie, H., Zhang, H., Peng, Y., Yuan, L., Jiang, Y., & Liao, E.-Y. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.05.006 · Cited by 12
“It regulates bone formation by integrating with leptin receptors located in the hypothalamus [17,26,27] and promoting bone resorption [28] through the sympathetic nervous system.”
Background
The osteoporosis revolution marches on
Raisz, L. G. (2007) · Journal of Orthopaedic Science · doi:10.1007/s00776-007-1133-2 · Cited by 13
Waking Up the Stem Cell Niche
Wolf, D., & Ley, K. F. (2015) · Circulation Research · doi:10.1161/circresaha.114.305678 · Cited by 12
CART deficiency increases body weight but does not alter bone strength.
Bartell, S. M., Isales, C. M., Baile, C. A., Kuhar, M. J., & Hamrick, M. W. (2008) · PubMed · Cited by 12
Bone biomarkers of ovariectomised rats after leptin therapy
Khaled, A., & Hamdy, M. (2013) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.4149/bll_2013_064 · Cited by 11
“Leptin also inhibits bone resorption by the stimulation of sympathetic nervous system and CART (cocaine amphetamine regulated transcript) (Elefteriou et al, 2005).”
Circadian clock and bone biology
Hirai, T. (2017) · Journal of Oral Biosciences · doi:10.1016/j.job.2017.06.001 · Cited by 12
Subcutaneous Fat and Body Fat Mass Have Different Effects on Bone Development at the Forearm in Children and Adolescents
Fricke, O., Land, C., Semler, O., Tutlewski, B., Stabrey, A., Remer, T., & Schöenau, E. (2008) · Calcified Tissue International · doi:10.1007/s00223-008-9129-2 · Cited by 12
“Leptin and adiponectin are hormones whose essential relationship to skeletal development and bone formation has been described in previous studies [5–9].”
Unraveling the Bone–Brain Communication Network
Hansda, S., & Das, H. (2025) · Biology · doi:10.3390/biology14091279 · Cited by 13
“The sympathetic nervous system favors bone resorption by increasing the expression in osteoblast progenitor cells of CART and related signaling molecules [171].”

Authors: Elefteriou, F., Ahn, J. D., Takeda, S., Starbuck, M., Yang, X., Liu, X., Kondo, H., Richards, W. G., Bannon, T. W., Noda, M., Clement, K., Vaisse, C., & Karsenty, G.
Affiliations: Baylor College of Medicine (US)
Tokyo Medical and Dental University (JP)
Amgen (United States) (US)
University of California, San Francisco (US)
ORCID: Elefteriou, Florent
Yang, Xiangli
Liu, Xiuyun
Kondo, Hisataka
Richards, William G.
Noda, Masaki
Vaisse, Christian
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-02-20
Volume: 434
Issue: 7032
Pages: 514-520
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03398
OpenAlex: W1997508587
Cited by: 1,311
References: 17
Citations by year: 2026: 45 · 2025: 46 · 2024: 55 · 2023: 43 · 2022: 38 · 2021: 59 · 2020: 51 · 2019: 48 · 2018: 51 · 2017: 52 · 2016: 53 · 2015: 69 · 2014: 83 · 2013: 67 · 2012: 84
FWCI: 30.49
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK060540)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords: leptin, bone resorption, bone remodeling, sympathetic nervous system, osteoclastogenesis, RANKL, beta2-adrenergic receptor, protein kinase A, osteoblasts, gonadectomy, osteoporosis, ob/ob mice, gonadal failure
MeSH terms: Cocaine- and Amphetamine-Regulated Transcript Protein, Amino Acid Sequence, Animals, Bone Resorption, Carrier Proteins, Cell Line, Child, Child, Preschool, Humans, Male, Membrane Glycoproteins, Models, Neurological, Neoplasm Proteins, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, Sympathetic Nervous System, Transcription Factors, Signal Transduction, Gene Deletion, Cyclic AMP-Dependent Protein Kinases, Receptors, Adrenergic, beta-2, Response Elements, Leptin, Receptor, Melanocortin, Type 4, Mice, Activating Transcription Factor 4, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, Receptors, Leptin

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Leptin regulation of bone resorption by the sympathetic nervous system and CART

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