Leptin regulation of bone resorption by the sympathetic nervous system and CART
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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From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [101]
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“Although both of these inputs induce RANKL in a cAMP-dependent manner in osteoblastic cells, SNS-induced RANKL up-regulation requires ATF4, whereas PTH-induced RANKL does not (Elefteriou et al. 2005).”
BackgroundQasim, A., Turcotte, M., de Souza, R. J., Samaan, M. C., Champredon, D., Dushoff, J., Speakman, J. R., & Meyre, D. (2018) · Obesity Reviews · doi:10.1111/obr.12625 · Cited by 241 · see citing works
“among individuals carrying at least one mutated allele) (146,147).”
BackgroundAdiponectin Regulates Bone Mass via Opposite Central and Peripheral Mechanisms through FoxO1
Kajimura, D., Lee, H. W., Riley, K. J., Arteaga‐Solis, E., Ferron, M., Zhou, B., Clarke, C. J., Hannun, Y. A., DePinho, R. A., Guo, X.-D. E., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.009 · Cited by 238 · see citing works
“Since the sympathetic tone enhances bone resorption by increasing Rankl expression (Elefteriou et al., 2005), we speculate that the high sympathetic activity seen in Adiponectin / mice antagonizes the consequence on Rankl expression of the absence of adiponectin signaling in osteoblasts.”
InfluentialSelf-citationA paradigm of integrative physiology, the crosstalk between bone and energy metabolisms
Confavreux, C. B., Levine, R. L., & Karsenty, G. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2009.04.004 · Cited by 233 · see citing works
“The second one reducing bone resorption uses CART to decrease RankL expression in osteoblasts through a yet incompletely deciphered pathway (Elefteriou et al., 2005).”
BackgroundInfluentialSelf-citationSouza, M. J. D., West, S., Jamal, S. A., HAWKER, G. A., Gundberg, C. M., & Williams, N. I. (2008) · Bone · doi:10.1016/j.bone.2008.03.013 · Cited by 236 · see citing works
Elefteriou, F., Benson, M. D., Sowa, H., Starbuck, M. W., Liu, X., Ron, D., Parada, L. F., & Karsenty, G. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.10.010 · Cited by 234 · see citing works
“, bone formation, and for osteoclast differentiation (Elefteriou et al., 2005; Yang et al., 2004).”
BackgroundMethodInfluentialSelf-citationBiver, E., Salliot, C., Combescure, C., Gossec, L., Hardouin, P., Legroux-Gérot, I., & Cortet, B. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0047 · Cited by 229 · see citing works
Depression induces bone loss through stimulation of the sympathetic nervous system
Yirmiya, R., Goshen, I., Bajayo, A., Kreisel, T., Feldman, S., Tam, J., Trembovler, V., CSERNUS, V. J., Shohami, E., & Bab, I. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604234103 · Cited by 231 · see citing works
Regulation of bone remodeling by the central and peripheral nervous system
Elefteriou, F. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.03.016 · Cited by 229 · see citing works
Self-citationLeptin and the sympathetic connection of fat to bone
Hamrick, M. W., & Ferrari, S. (2007) · Osteoporosis International · doi:10.1007/s00198-007-0487-9 · Cited by 223 · see citing works
“These effects appear to be primarily, if not uniquely, mediated by beta2 adrenergic receptors expressed in osteoblasts [59], as several investigators, including ourselves, failed to detect significant expression of beta1 and beta3 adrenergic receptor genes (ADRB1, ADRB3) in primary osteoblastic cells from mouse calvar…”
InfluentialYoshizawa, T., Hinoi, E., Jung, D. Y., Kajimura, D., Ferron, M., Seo, J. H., Graff, J. M., Kim, J. K., & Karsenty, G. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39366 · Cited by 218 · see citing works
Self-citationThe role of osteocalcin in the endocrine cross-talk between bone remodelling and energy metabolism
Ducy, P. F. (2011) · Diabetologia · doi:10.1007/s00125-011-2155-z · Cited by 219 · see citing works
“bone resorption) [4, 25].”
miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2
Wei, J., Shi, Y., Zheng, L., Zhou, B., Inose, H., Wang, J., Guo, X.-D. E., Grosschedl, R., & Karsenty, G. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201201057 · Cited by 219 · see citing works
“For quantifying gene expression, unless specified in the figure legend, femurs and tibiae of 3-mo-old”
Self-citationGrässel, S. (2014) · Arthritis Research & Therapy · doi:10.1186/s13075-014-0485-1 · Cited by 217 · see citing works
“VIP has been demonstrated to play an important role in the control of osteoclast formation because destruction of nerves expressing VIP by guanethidine treatment increases the number of osteoclasts [69].”
BackgroundEffects of Leptin on the Skeleton
Reid, I. R., Baldock, P. A., & Cornish, J. (2018) · Endocrine Reviews · doi:10.1210/er.2017-00226 · Cited by 215 · see citing works
Stearoyl-CoA desaturase: rogue or innocent bystander?
Hodson, L., & Fielding, B. A. (2012) · Progress in Lipid Research · doi:10.1016/j.plipres.2012.08.002 · Cited by 215 · see citing works
“Animal work has shown that the PPARc pathway, which is the dominant regulator of adipogenesis, inhibits osteoblast differentiation [239], and that leptin, an anorexigenic metabolic hormone that is secreted in proportion to fat mass, is a regulator of both bone formation and resorption [240,241].”
BackgroundCrosstalk between Bone and Nerves within Bone
Wan, Q., Qin, W., Ma, Y., Shen, M., Li, J., Zhang, Z., Chen, J., Tay, F. R., Niu, L., & Jiao, K. (2021) · Advanced Science · doi:10.1002/advs.202003390 · Cited by 212 · see citing works
Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms
Wongdee, K. (2011) · World Journal of Diabetes · doi:10.4239/wjd.v2.i3.41 · Cited by 213 · see citing works
Marrow Adipose Tissue: Trimming the Fat
Scheller, E. L., Cawthorn, W. P., Burr, A. A., Horowitz, M. C., & MacDougald, O. A. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.03.016 · Cited by 202 · see citing works
Nerves in Bone: Evolving Concepts in Pain and Anabolism
Brazill, J. M., Beeve, A. T., Craft, C. S., Ivanusic, J. J., & Scheller, E. L. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3822 · Cited by 206 · see citing works
“(27,118) Mechanistically, sympathetic activity induces osteopenia as a result of activation of the β2‐AR on osteoblasts, which suppresses osteoblast proliferation and promotes release of RANKL to support osteoclastogenesis.”
BackgroundCentral control of bone remodeling by neuromedin U
Sato, S., Hanada, R., Kimura, A., Abe, T., Μatsumoto, T., Iwasaki, M., Inose, H., Ida, T., Mieda, M., Takeuchi, Y., et al. (2007) · Nature Medicine · doi:10.1038/nm1640 · Cited by 205 · see citing works
“Leptin inhibits bone formation by binding to its receptors located in hypothalamus and thereby activating the sympathetic nervous system (SNS), which requires the adrenergic β2 receptors (Adrb2) expressed in osteoblast”
BackgroundSelf-citationBone remodelling: its local regulation and the emergence of bone fragility
Martin, T. J., & Seeman, E. (2008) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2008.07.006 · Cited by 202 · see citing works
Mak, K. K., Bi, Y., Wan, C., Chuang, P.-T., Clemens, T., Young, M., & Yang, Y. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.02.003 · Cited by 202 · see citing works
“Since PTH can still activate RANKL expression in the ATF4 À/À osteoblasts (Elefteriou et al., 2005), we tested our hypothesis that PTHrP promotes RANKL expression by activating PKA and its target transcription factor CREB.”
BackgroundInfluentialThe cannabinoid CB1 receptor regulates bone formation by modulating adrenergic signaling
Tam, J., Trembovler, V., Marzo, V. D., Petrosino, S., Leo, G., Alexandrovich, A., Regev, E., Casap, N., Shteyer, A., Ledent, C. A., et al. (2007) · The FASEB Journal · doi:10.1096/fj.06-7957com · Cited by 201 · see citing works
Campbell, J. P., Karolak, M. R., Ma, Y., Perrien, D. S., Masood-Campbell, S. K., Penner, N. L., Munoz, S. A., Zijlstra, A., Yang, X., Sterling, J. A. R., et al. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001363 · Cited by 203 · see citing works
“The osteoblastic niche and the b2 adrenergic receptor (b2AR) appear to be central and necessary mediators of such sympathetic-driven skeletal processes, generating cytokines that play pivotal roles in stimulating osteoclast formation and hematopoietic cell trafficking, including SDF1 [15,16] and RANKL (receptor activa…”
BackgroundMethodSelf-citationSignaling Networks that Control the Lineage Commitment and Differentiation of Bone Cells
Soltanoff, C. S., Yang, S., Chen, W., & Li, Y. (2009) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v19.i1.10 · Cited by 196 · see citing works
Serum osteocalcin concentrations in relation to glucose and lipid metabolism in Chinese individuals
Zhou, M., Ma, X., Li, H., Pan, X., Tang, J., Gao, Y., Hou, X., Lu, H., Bao, Y., & Jia, W. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0585 · Cited by 193 · see citing works
AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass
Shah, M., Kola, B., Bataveljic, A., Arnett, T. R., Viollet, B., Saxon, L., Korbonits, M., & Chenu, C. (2010) · Bone · doi:10.1016/j.bone.2010.04.596 · Cited by 193 · see citing works
“While communication between fat and bone was debated for a long time, new evidence has emerged with the discovery that the adipocytesecreted hormone leptin inhibits bone formation through hypothalamic and sympathetic nervous system (SNS) relays [1,2].”
BackgroundResultInfluentialCooperation of β 2 ‐ and β 3 ‐adrenergic receptors in hematopoietic progenitor cell mobilization
Méndez‐Ferrer, S., Battista, M., & Frenette, P. S. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05390.x · Cited by 194 · see citing works
Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual
Bajayo, A., Bar, A., Dénes, Á., Bachar, M., Kram, V., Attar-Namdar, M., Zallone, A. Z., Kovács, K., Yirmiya, R., & Bab, I. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206061109 · Cited by 194 · see citing works
“Bone mass is regulated by an intricate system including central cues, so far shown to be transmitted mainly via the sympathetic nervous system (SNS), which tonically restrains bone formation and stimulates bone resorption, thus downregulating bone mass accrual (2, 3).”
BackgroundBone and skeletal muscle: neighbors with close ties
DiGirolamo, D. J., Kiel, D. P., & Esser, K. A. (2013) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1969 · Cited by 193 · see citing works
“这可能代表骨和肌肉协调质量的一条共同分子途径。 尽管大量证据支持协调骨与肌肉质量的生化联 系,针对这一假想机制本质的许多重要问题仍有待 商榷。骨和肌肉对机械负荷的反应是平行发生,还 是肌肉作为物理运动的初级响应器而将次级信号转 导给骨骼?机械负荷理论所假定的机械信号本质为 何? [130] 更进一步,骨细胞是否作为初级机械感受器, 如何将机械信号转化为骨重塑的生化编配?肌肉是 否起着机械—内分泌转换器的作用,肌肉的机械活 动在何处激发旁分泌 / 内分泌效应器,何者进一步 影响骨的发育?从快速发展的 myokine 研究领域和 其他生理环境中器官系统相互作用的研究来看,这 似乎是一个越来越有吸引力的假说。最后,由于神 经系统在调节正…”
Reciprocal regulation of bone and energy metabolism
Lee, N. K., & Karsenty, G. (2008) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2008.02.006 · Cited by 190 · see citing works
Self-citationIliopoulos, D., Malizos, K. N., & Tsezou, A. (2007) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2007.069377 · Cited by 190 · see citing works
Neurovascular coupling in bone regeneration
Qin, Q., Lee, S., Patel, N., Walden, K., Gomez-Salazar, M. A., Lévi, B., & James, A. W. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00899-6 · Cited by 199 · see citing works
DISC1-binding proteins in neural development, signalling and schizophrenia
Bradshaw, N. J., & Porteous, D. J. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.12.027 · Cited by 188 · see citing works
“Downstream effects of NRG1 signalling include inducing the expression and activity of ATF4 (Talukder et al., 2000).”
InfluentialGenetic determination of the cellular basis of the sympathetic regulation of bone mass accrual
Kajimura, D., Hinoi, E., Ferron, M., Kode, A., Riley, K. J., Zhou, B., Guo, X.-D. E., & Karsenty, G. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20102608 · Cited by 187 · see citing works
“As it is the case in mice lacking Adr2 in all cells (Elefteriou et al., 2005), Adr2osb/ mice had a normal bone mass until 12 wk of age (Fig.”
BackgroundInfluentialSelf-citationRegulation of bone formation and remodeling by G-protein-coupled receptor 48
Luo, J., Zhou, W., Zhou, X., Li, D., Weng, J., Yi, Z., Cho, S., Li, C., Yi, T., Wu, X., et al. (2009) · Development · doi:10.1242/dev.033571 · Cited by 178 · see citing works
Marrow fat metabolism is linked to the systemic energy metabolism
Lecka‐Czernik, B. (2011) · Bone · doi:10.1016/j.bone.2011.06.032 · Cited by 168 · see citing works
“On the other hand, β1-AR and β2-AR regulate osteoblasts function, whereas β3-AR is expressed in marrow adipocytes and may control lipolysis and energy production [7,21,48,59].”
InfluentialControl of Bone Remodeling by the Peripheral Sympathetic Nervous System
Elefteriou, F., Campbell, P. J., & Ma, Y. (2013) · Calcified Tissue International · doi:10.1007/s00223-013-9752-4 · Cited by 165 · see citing works
“Leptin N [41] nd N [72] : [74] nd N [46]”
InfluentialSelf-citationFu, Q., Manolagas, S., & O'Brien, C. A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00356-06 · Cited by 165 · see citing works
“Recent work by the Karsenty laboratory indicates that sympathetic nervous system signaling stimulates bone resorption by stimulating RANKL expression in immature osteoblastic cells via the ATF4 transcription factor, which binds a CRE-like element in the proximal RANKL promoter (9).”
BackgroundResultSelective leptin resistance revisited
Mark, A. L. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00180.2013 · Cited by 162 · see citing works
“The surprising finding was that leptin also increased SNA to the kidney, adrenal gland, and hindlimb, (29, 58, 78, 88), and it has subsequently been shown to regulate sympathetic activity to liver (153), bone (31), and the splanchnic circulation (75).”
- 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
- Venue
- Nature
- Published
- 2005-02-20
- Volume
- 434
- Issue
- 7032
- Pages
- 514-520
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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