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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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“A polymorphism of the first intron of the gene coding for the type I collagen α1 chain and increased levels of homocysteine can influence fracture risk independent of BMD”
From Pathogenesis of osteoporosis: concepts, conflicts, and prospects (2005) · cites this paper as [101]
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Self-citationLeptin Regulates Bone Formation via the Sympathetic Nervous System
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Involvement of Neuronal Cannabinoid Receptor CB1 in Regulation of Bone Mass and Bone Remodeling
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“These fibers release norepinephrine, thus potently mediating central signals that restrain bone formation and stimulate bone resorption (Elefteriou et al., 2005).”
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BackgroundThe Bone-Adipose Axis in Obesity and Weight Loss
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“This effect seems to take place through the regulation of bone formation and resorption by the β2-adrenergic receptor [22], the neuropeptide cocaine and amphetamine-regulated transcript (CART) [ 23 ] and the clock genes, which determine circadian rhythms [24].”
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Bözec, A., Bakiri, L., Jiménez, M., Schinke, T., Amling, M., & Wagner, E. F. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201002111 · Cited by 149
“It is required for osteoblast-specific expression of osteocalcin (Oc) and for posttranscriptional regulation of type I collagen (col1) synthesis, the main constituents of bone matrix, as well as for transcriptional control of Rankl expression (Yang et al., 2004; Elefteriou et al., 2005).”
Fat targets for skeletal health
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Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones
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“Sympathetic tone is fulfilled by releasing norepinephrine and epinephrine, and an increase in epinephrine level could cause decreased bone formation (47, 48).”
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ResultThe Central Regulation of Bone Mass, The First Link between Bone Remodeling and Energy Metabolism
Karsenty, G., & Oury, F. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1030 · Cited by 144
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“We do not have enough cases to analyze potential differences between β selective and β non-selective blockers as suggested by the β adrenergic KO mice [10].”
BackgroundInfluentialSalt-Inducible Kinases: Physiology, Regulation by cAMP, and Therapeutic Potential
Wein, M. N., Foretz, M., Fisher, D. E., Xavier, R. J., & Kronenberg, H. M. (2018) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2018.08.004 · Cited by 138
“CREB and related bZIP factors drive RANKL gene expression [52,53].”
BackgroundMolecular bases of the sympathetic regulation of bone mass
Takeda, S., & Karsenty, G. (2008) · Bone · doi:10.1016/j.bone.2008.01.005 · Cited by 140
“While these manipulations increased the number of osteoclasts and decreased bone mass in control mice, they failed to have any of these effects in β2Ar-deficient or -blocked mice, thus illustrating the importance of sympathetic regulation of bonemass [7].”
BackgroundInfluentialSelf-citationIs obesity in women protective against osteoporosis?
Migliaccio, S., Greco, E. A., Fornari, F., Donini, L. M., & Lenzi (2011) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s11920 · Cited by 143
“Interestingly, type 4 α-melanocyte-stimulating hormone receptor knockout mice have high bone mass due to decreased bone resorption.(82)”
BackgroundDissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo
Shi, Y., Yadav, V. K., Suda, N., Liu, X. S., Guo, X.-D. E., Myers, M. G., & Karsenty, G. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808701106 · Cited by 139
“4 C and D), indicating that the Y985L mutation does not affect Cart expression as a complete inactivation of leptin signaling does (4).”
BackgroundInfluentialSelf-citationCART in the regulation of appetite and energy homeostasis
Lau, J., & Herzog, H. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00313 · Cited by 145
Targeting the ATF4 pathway in cancer therapy
Singleton, D. C., & Harris, A. L. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.728207 · Cited by 133
“Potent ATP-competitive inhibitors of PKA are also available including H-89 (4) and KT 5720 (5), although numerous PKA-independent effects have been reported suggesting these agents lack selectivity (Figure 2B) [51].”
BackgroundInfluentialEndocrine manifestations of eating disorders
Warren, M. P. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2304 · Cited by 134
Ellacott, K. L. J., & Cone, R. D. (2006) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2006.1861 · Cited by 138
Ablation of the Sam68 RNA Binding Protein Protects Mice from Age-Related Bone Loss
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Sympathetic β1-adrenergic signaling contributes to regulation of human bone metabolism
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“Relative mRNA levels of (A) RANKL (also known as TNFSF11), (B) OPG (also known as TNFRSF11B), (C) ADRB1, and (D) ADRB2 in hFOB cells treated for 2 hours with vehicle, dobutamine (β1-AR agonist), or salmeterol (β2-AR agonist).”
BackgroundInfluentialBiology Without Walls: The Novel Endocrinology of Bone
Karsenty, G., & Oury, F. (2011) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153233 · Cited by 142
Self-citationChanges in Skeletal Integrity and Marrow Adiposity during High-Fat Diet and after Weight Loss
Scheller, E. L., Khoury, B. M., Moller, K. L., Wee, N. K. Y., Khandaker, S., Kozloff, K. M., Abrishami, S., Zamarron, B. F., & Singer, K. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00102 · Cited by 137
“Although the direct effects of leptin may also promote osteoblast proliferation and differentiation (25, 48), the central effects of leptin have been shown to mediate the opposite effects, promoting cancellous bone loss via the sympathetic nervous system (23, 24).”
BackgroundBariatric surgery, bone loss, obesity and possible mechanisms
Brzozowska, M. M., Sainsbury, A., Eisman, J. A., Baldock, P. A., & Center, J. R. (2013) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01050.x · Cited by 128
Angiotensin II Type 2 Receptor Blockade Increases Bone Mass
Izu, Y., Mizoguchi, F., Kawamata, A., Hayata, T., Nakamoto, T., Nakashima, K., Inagami, T., Ezura, Y., & Noda, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807610200 · Cited by 128
Self-citationLong Bone Defect Models for Tissue Engineering Applications: Criteria for Choice
Horner, E. A., Kirkham, J., Wood, D. J., Curran, S., Smith, M. D., Thomson, B. M., & Yang, X. (2009) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2009.0224 · Cited by 124
“and Elefteriou et al.(45) stated that nerves (innervation) are critical for osteoblast function.”
Self-citationNeuronal signaling and the regulation of bone remodeling
Elefteriou, F. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5175-3 · Cited by 131
Self-citationOsteocytes Regulate Primary Lymphoid Organs and Fat Metabolism
Sato, M., Asada, N., Kawano, Y., Wakahashi, K., Minagawa, K., Kawano, H., Sada, A., Ikeda, K., Matsui, T., & Katayama, Y. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.09.014 · Cited by 126
“It is recognized that certain areas of the brain, such as the ventromedial hypothalamic nucleus (VMH) and arcuate nucleus (ARC), also control bone metabolism via the sympathetic nervous system in response to leptin signaling (Elefteriou et al., 2005; Takeda et al., 2002).”
BackgroundShi, Y., Oury, F., Yadav, V. K., Wess, J., Liu, X. S., Guo, X. E., Murshed, M., & Karsenty, G. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.01.005 · Cited by 126
“This signaling event triggers a decrease of the activityof thesympatheticnervoussystem(SNS),aknownnegative regulator of bone mass accrual acting through the b2 adrenergic receptor (Adrb2) present on osteoblasts (Elefteriou et al., 2005; Fu et al., 2005; Takeda et al., 2002).”
BackgroundSelf-citationNovel insights into the relationship between diabetes and osteoporosis
de Paula, F. J. A., Horowitz, M. C., & Rosen, C. J. (2010) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1135 · Cited by 125
PERK‐eIF2α‐ATF4‐CHOP Signaling Contributes to TNFα‐Induced Vascular Calcification
Masuda, M., Miyazaki‐Anzai, S., Levi, M., Ting, T. C., & Miyazaki, M. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000238 · Cited by 126
Osteoblastogenesis regulation signals in bone remodeling
Zuo, C., Huang, Y., Bajis, R., Sahih, M., Li, Y., Dai, K., & Zhang, X. (2012) · Osteoporosis International · doi:10.1007/s00198-012-1909-x · Cited by 129
“Additionally, the analysis of Adrb2-deficient mice reveals that the leptin-SNS pathway promotes bone resorption by increasing the expression of the osteoclast differentiation factor RANKL in osteoblast progenitor cells [96].”
BackgroundSpiegel, A., Kalinkovich, A., Shivtiel, S., Kollet, Ó., & Lapidot, T. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.10.006 · Cited by 123
Burwell, R. G., Aujla, R. K., Grevitt, M. P., Dangerfield, P., Moulton, A., Randell, T. L., & Anderson, S. (2009) · Scoliosis · doi:10.1186/1748-7161-4-24 · Cited by 130
“In the last decade it was shown initially in mice, that the central nervous system regulates bone remodeling, and more recently longitudinal bone growth via the sympathetic nervous system linking leptin-responsive hypothalamic neurons to bone tissue [187-198].”
BackgroundOury, F., Yadav, V. K., Wang, Y., Zhou, B., Liu, X. S., Guo, X.-D. E., Tecott, L. H., Schütz, G., Means, A. R., & Karsenty, G. (2010) · Genes & Development · doi:10.1101/gad.1977210 · Cited by 122
“Briefly, following its binding to the Htr2c receptor in neurons of the ventromedial hypothalamic (VMH) nuclei, serotonin favors bone mass accrual by decreasing activity of the sympathetic nervous system, a negative regulator of this function (Takeda et al. 2002; Elefteriou et al. 2005), while, following its binding to…”
BackgroundInfluentialSelf-citationThe Effect of Leptin on Bone - an Evolving Concept of Action
Cirmanová, V., Bayer, M., Stárka, L., & Zajíčková, K. (2008) · Physiological Research · doi:10.33549/physiolres.931499 · Cited by 127
Adiponectin Inhibits Osteoclastogenesis and Bone Resorption via APPL1-mediated Suppression of Akt1
Tu, Q., Zhang, J., Dong, L., Saunders, E., Luo, E., Tang, J., & Chen, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.152405 · Cited by 122
Transient receptor potential vanilloid 4 deficiency suppresses unloading‐induced bone loss
Mizoguchi, F., Mizuno, A., Hayata, T., Nakashima, K., Heller, S., Ushida, T., Sokabe, M., Miyasaka, N., Suzuki, M., Ezura, Y., et al. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21374 · Cited by 126
“In fact, sympathetic tone is involved in bone homeostasis via suppression of bone formation by osteoblasts and activation of resorption by osteoclasts (Takeda et al., 2002; Elefteriou et al., 2005).”
BackgroundSelf-citationThe Central Nervous System and Bone Metabolism: An Evolving Story
Dimitri, P., & Rosen, C. J. (2016) · Calcified Tissue International · doi:10.1007/s00223-016-0179-6 · Cited by 124
“Leptin acts via the SNS and osteoblast Adrb2 receptors to increase the expression of Rankl and thus promote osteoclast proliferation, whilst conversely, leptin increases the expression of CART which in turn reduces bone resorption by yet to be determined pathways [31].”
BackgroundInfluentialThe Relationship Between Bone and Reproductive Hormones Beyond Estrogens and Androgens
Mills, E., Yang, L. Y., Nielsen, M. F., Kassem, M. S., Dhillo, W. S., & Comninos, A. N. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab015 · Cited by 136
“How bone remodeling is coupled specifically to energy metabolism has been the focus of several seminal studies revealing the importance of leptin in the interplay between bone and the central nervous system (5-7).”
BackgroundNeuro–bone tissue engineering: emerging mechanisms, potential strategies, and current challenges
Sun, W., Ye, B., Chen, S., Zeng, L., Lu, H., Wan, Y., Gao, Q. H., Chen, K., Qu, Y., Wu, B., et al. (2023) · Bone Research · doi:10.1038/s41413-023-00302-8 · Cited by 137
“85 Additionally, after ovariectomy, nerve density in rats decreased signi fi cantly, supporting the connection between the nervous system and bone loss following ovariectomy.”
BackgroundSkeletal phenotype of the leptin receptor–deficient db / db mouse
Williams, G. A., Callon, K. E., Watson, M., Costa, J. L., Ding, Y., Dickinson, M., Wang, Y., Naot, D., Reid, I. R., & Cornish, J. (2011) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.367 · Cited by 119
“In contrast to these findings, the Karsenty group demonstrated that infusion of leptin into the third ventricle causes bone loss in leptin-deficient and wild-type mice through inhibition of bone formation((12)) and stimulation of bone resorption.((39)) However, this is accompanied by a dramatic loss of body weight((12…”
ResultThe serotonin 5‐HT 2B receptor controls bone mass via osteoblast recruitment and proliferation
Collet, C., Schiltz, C., Geoffroy, V., Maroteaux, L., Launay, J., & de Vernejoul, M. C. (2007) · The FASEB Journal · doi:10.1096/fj.07-9209com · Cited by 119
Leptin regulates chondrocyte differentiation and matrix maturation during endochondral ossification
Kishida, Y., Hirao, M., Tamai, N., Nampei, A., Fujimoto, T., Nakase, T., Shimizu, N., Yoshikawa, H., & Myoui, A. (2005) · Bone · doi:10.1016/j.bone.2005.05.009 · Cited by 118
“A very recent report showed that leptin also regulates bone resorption through osteoblast function to support osteoclastogenesis in a complicated manner via the sympathetic nerve system and other molecules [39].”
BackgroundThe role of estrogen receptor α in the regulation of bone and growth plate cartilage
Börjesson, A., Lagerquist, M. K., Windahl, S. H., & Ohlsson, C. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1317-1 · Cited by 122
“In addition, mice lacking the β2-adrenergic receptor, which binds the main sympathetic neurotransmitter noradrenaline, were resistant to the central bone-reducing effects of leptin, demonstrating that central leptin signaling may exert its negative effects on bone via the sympathetic nervous system [82, 83].”
Pierroz, D. D., Bonnet, N., Bianchi, E. N., Bouxsein, M., Baldock, P. A. J., Rizzoli, R., & Ferrari, S. (2012) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.1594 · Cited by 118
“These observations strongly contrast with Adrb2 / mice, which do not present a bone phenotype during growth and develop a higher trabecular bone volume by about 6 months of age.((14)) Here we also confirm the high vertebral bone mass phenotype of Adrb2 / mice and further demonstrate that, contrarily to Adrb1 / and Adr…”
BackgroundResultInfluentialAMP-activated protein kinase pathway and bone metabolism
Jeyabalan, J., Shah, M., Viollet, B., & Chenu, C. (2011) · Journal of Endocrinology · doi:10.1530/joe-11-0306 · Cited by 120
“We also examined the effect of propranolol, a b-adrenergic receptor antagonist that stimulates bone formation in vivo (Elefteriou et al. 2005), on AMPK activity in ROS 17/2.”
BackgroundImpacts of Psychological Stress on Osteoporosis: Clinical Implications and Treatment Interactions
Kelly, R. R., McDonald, L. T., Jensen, N. R., Sidles, S. J., & LaRue, A. C. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00200 · Cited by 125
“There is also some evidence to suggest that activation of the sympathetic nervous system, commonly associated with chronic psychological stress, affects the peripheral expression of RANKL on osteoblasts (118, 119) and T cells (120).”
BackgroundFunctional α1‐ and β2‐adrenergic receptors in human osteoblasts
Huang, H., Brennan‐Speranza, T. C., Muir, M. M., & Mason, R. S. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21761 · Cited by 115
“…replication or protein synthesis in fibroblasts while phenylephrine also enhanced numbers of cardiac fibroblasts (Leicht et al., 2000, 2003; Faber et al., 2001; Zhang and Faber, 2001). a1B-ARs, in particular, mediated the norepinephrine-induced growth of adventitial fibroblasts in aorta…”
BackgroundNeural regulation of bone and bone marrow
Maryanovich, M., Takeishi, S., & Frenette, P. S. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031344 · Cited by 114
“Similar to deletion of leptin or Lepr, β2-AR deletion resulted in increased bone mass phenotype; however, ICV infusion of leptin in these mice failed to rescue the increased bone mass (Elefteriou et al. 2005; Bonnet et al. 2008).”
BackgroundResultInfluentialRoles of leptin in bone metabolism and bone diseases
Chen, X., & Yang, T. (2015) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-014-0569-7 · Cited by 118
“Several reports demonstrated that ATF4, a protein characterized as CREB2, mediated sympathetic signaling in osteoblasts [8, 13].”
BackgroundInfluentialMajor Depression Is a Risk Factor for Low Bone Mineral Density: A Meta-Analysis
Yirmiya, R., & Bab, I. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.03.016 · Cited by 117
The crosstalk between bone remodeling and energy metabolism: A translational perspective
Karsenty, G., & Khosla, S. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.04.010 · Cited by 113
Self-citationMedial arterial calcification in diabetes and its relationship to neuropathy
Jeffcoate, W. J., Rasmussen, L. M., Hofbauer, L. C., & Game, F. L. (2009) · Diabetologia · doi:10.1007/s00125-009-1521-6 · Cited by 113
“Leptin stimulates sympathetic β2-adrenergic signalling, which inhibits osteoblastic function and favours bone resorption [81].”
BackgroundThe adverse skeletal effects of selective serotonin reuptake inhibitors
Tsapakis, E.-M., Gamie, Z., Tran, G. T., Adshead, S., Lampard, A. L., Mantalaris, A., & Tsiridis, E. E. (2011) · European Psychiatry · doi:10.1016/j.eurpsy.2010.10.006 · Cited by 115
“Figure adapted from Figure adapted from [58,16].”
BackgroundInfluentialMartin, A., David, V., Malaval, L., Lafage-Proust, M.-H., Vico, L., & Thomas, T. (2007) · Endocrinology · doi:10.1210/en.2006-1541 · Cited by 111
“This is also consistent with the central control of leptin on bone resorption, which is mediated by a combination of both sympathetic nervous system and CART (cocaine amphetamine-regulated transcript) effects (39).”
BackgroundHallmarks of peripheral nerve function in bone regeneration
Tao, R., Mi, B., Hu, Y., Lin, S., Xiong, Y., Lu, X., Panayi, A. C., Li, G., & Liu, G. (2023) · Bone Research · doi:10.1038/s41413-022-00240-x · Cited by 110
“Further research showed that low sympathetic tone resulting from leptin deficiency increased bone mass by regulating the proliferation of osteoblasts and the expression of the osteoclast differentiation factor RANKL in osteoblasts.(144,173) Poor peripheral nerve function is also related to lower bone mineral density i…”
BackgroundEndocrine role of bone: recent and emerging perspectives beyond osteocalcin
Oldknow, K. J., MacRae, V. E., & Farquharson, C. (2015) · Journal of Endocrinology · doi:10.1530/joe-14-0584 · Cited by 112
Ortuño, M. J., Robinson, S. T., Subramanyam, P., Paone, R., Huang, Y.-Y., Guo, X.-D. E., Colecraft, H. M., Mann, J. J., & Ducy, P. F. (2016) · Nature Medicine · doi:10.1038/nm.4166 · Cited by 113
“In agreement with the role of sympathetic signaling in osteoblasts 39,40 , the Tnfrsf11b/Tnfsf11 ratio, and more specifically the expression of the gene encoding RANKL, was normalized in mice co-treated with Flx and propranolol compared to those treated with Flx alone although their sympathetic…”
Neuronal Induction of Bone‐Fat Imbalance through Osteocyte Neuropeptide Y
Zhang, Y., Chen, C., Liu, Y., Rao, S., Tan, Y., Qian, Y., Xia, K., Huang, J., Liu, X., Hong, C., et al. (2021) · Advanced Science · doi:10.1002/advs.202100808 · Cited by 110
Self-citationDose Effects of Propranolol on Cancellous and Cortical Bone in Ovariectomized Adult Rats
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“Our results with animals treated by 20 mg of propranolol caution the findings obtained on 1 2-adrenergic receptor KO mice in appendicular bone (tibia, femur), where no preventive effects of propranolol on BMD and in metaphysis architecture were shown (Elefteriou et al., 2005a; Pierroz et al., 2005).”
BackgroundResultNew Roles of Carboxypeptidase E in Endocrine and Neural Function and Cancer
Cawley, N. X., Wetsel, W. C., Murthy, S. R. K., Park, J. J., Pacák, K., & Loh, Y. P. (2012) · Endocrine Reviews · doi:10.1210/er.2011-1039 · Cited by 114
“e, Leptin activates the hypothalamus to express the anorexigenic peptides, -MSH and CART, and decrease the orexigenic peptides, NPY and AGRP, as well as to stimulate the sympathetic nervous system (334, 335).”
BackgroundBone Remodeling, Energy Metabolism, and the Molecular Clock
Rosen, C. J. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.12.004 · Cited by 107
“Two receptors for melanocortin are present in the arcuate nucleus, and gene deletion of one leads to mice with high bone mass and suppressed bone resorption (Elefteriou et al., 2005).”
BackgroundWu, J. Y., Aarnisalo, P., Bastepe, M., Sinha, P. S., Fulzele, K. S., Selig, M. K., Chen, M., Poulton, I. J., Purton, L. E., Sims, N. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46406 · Cited by 106
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“However, once again there were not complete microarchitectural and histomorphometric analyses of leptin-treated Adrb2−/− mice.”
BackgroundInfluentialRoepke, T. A., Bosch, M. A., Rick, E. A., Lee, B., Wagner, E. J., Seidlova-Wuttke, D., Wuttke, W., Scanlan, T. S., Rønnekleiv, O. K., & Kelly, M. J. (2010) · Endocrinology · doi:10.1210/en.2010-0573 · Cited by 103
Bone Cell Bioenergetics and Skeletal Energy Homeostasis
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“In subsequent studies, hypothalamic leptin signaling was shown to govern both arms of the bone remodeling process via sympathetic control of Atf4-mediated expression of RANKL and clock gene-mediated regulation of osteoblast proliferation (86, 107).”
BackgroundMECHANISMS IN ENDOCRINOLOGY: The endocrine role of the skeleton: background and clinical evidence
Theiler‐Schwetz, V., Pieber, T. R., & Obermayer-Pietsch, B. M. (2012) · European Journal of Endocrinology · doi:10.1530/eje-12-0030 · Cited by 104
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“Namely, blockade of beta2-adrenoreceptors caused bone formation [113], while stimulation of beta2-adrenoreceptors resulted in bone resorption [115].”
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Leptin Functions Peripherally to Regulate Differentiation of Mesenchymal Progenitor Cells
Scheller, E. L., Song, J., Dishowitz, M. I., Soki, F. N., Hankenson, K. D., & Krebsbach, P. H. (2010) · Stem Cells · doi:10.1002/stem.432 · Cited by 106
Niedźwiedzki, T., & Filipowska, J. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0067 · Cited by 105
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“This is consistent with both the positive expression of Adrb2R on rat osteoblasts and the bone phenotype observed in Adrb2R deficient mice (Takeda et al., 2002; Elefteriou et al., 2005).”
BackgroundResultInfluentialLassot, I., Estrabaud, E., Emiliani, S., Benkirane, M., Bénarous, R., & Margottin-Goguet, F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505294200 · Cited by 97
Activating transcription factor 4 regulates osteoclast differentiation in mice
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The Impact of Childhood Obesity on Skeletal Health and Development
Dimitri, P. (2019) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes.2019.28.1.4 · Cited by 97
“the ventromedial hypothalamus and through efferent sympathetic pathways exerting an antiosteogenic effect through く2 adrenergic receptors in osteoblasts.(78,79) Later studies revealed that sympathetic”
BackgroundJiang, S., Yan, F., Hu, J., Mohammed, A. A. A., & Cheng, H. W. (2021) · Animals · doi:10.3390/ani11061494 · Cited by 97
“Both strains of Lactobacillus and Bifidobacterium have been used as probiotics for increasing bone health in humans and various animals [56,57,205].”
BackgroundAitken, S. J., Landao‐Bassonga, E., Ralston, S. H., & Idris, A. I. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.11.012 · Cited by 99
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The effects of gut microbiota on appetite regulation and the underlying mechanisms
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How Does Body Fat Influence Bone Mass in Childhood? A Mendelian Randomization Approach
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“MC4R is known to be a major regulator of cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus, the absence of which in mice leads to a low bone mass phenotype secondary to increased bone resorption.((33)) Moreover, children heterozygous for an MC4R loss of function mutation were found to have incre…”
BackgroundContributions of the Host Microenvironment to Cancer-Induced Bone Disease
Olechnowicz, S. W. Z., & Edwards, C. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2645 · Cited by 98
“For example, leptin has been shown to influence SNS signaling through the hypothalamus to cause a wide variety of effects, such as decreased osteoblast proliferation and increased RANKL and osteoclast activity (57).”
Ma, Y., Nyman, J. S., Tao, H., Moss, H. H., Yang, X., & Elefteriou, F. (2011) · Endocrinology · doi:10.1210/en.2010-0881 · Cited by 92
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Interactions between central nervous system and peripheral metabolic organs
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“…and systematic studies on regulating bone metabolism in the VMH, and found that VMH was regulated by leptin, it regulated bone metabolism through the sympathetic nervous system (Ducy et al., 2000; Elefteriou et al., 2005; Shi et al., 2008; Takeda et al., 2002; Yadav et al., 2009).”
BackgroundInfluentialHematopoietic Stem Cell Trafficking
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“After abolishing sympathetic influence on bone metabolism one would expect a high bone mass phenotype (HBM) as seen in studies using β2-adrenergic receptor deficient or Leptin deficient mice (Takeda et al., 2002; Elefteriou et al., 2005).”
BackgroundRegulation of Skeletal Homeostasis
Zaidi, M., Yuen, T., Sun, L., & Rosen, C. J. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00050 · Cited by 95
The Role of Nerves in Skeletal Development, Adaptation, and Aging
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“Function of ANS in Bone The major function of the ANS on the skeleton is restraint of bone remodeling (37).”
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Self-citationThe New Field of Neuroskeletal Biology
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“Low Cart expression in ob/ob mice accompanies the increased bone resorption observed in these mice, while increased hypothalamic Cart expression in obese and hyperleptinemic melanocortin 4 receptor (Mc4r)-deficient mice correlates with their low bone resorption and high bone mass [ 69 ].”
BackgroundResultInfluentialSelf-citationThe Impact of Fat and Obesity on Bone Microarchitecture and Strength in Children
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Murine Osteoclast Formation and Function: Differential Regulation by Humoral Agents
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The role of the sympathetic nervous system in controlling bone metabolism
Togari, A., Arai, M., & Kondo, A. (2005) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.9.5.931 · Cited by 88
“Targets (2005) 9(5) The above-mentioned findings are strongly supported by recent experiments from Karsenty’s group [32].”
Augmented capacity for peripheral serotonin release in human obesity
Young, R. L., Lumsden, A. L., Martin, A. M., Schober, G., Pezos, N., Thazhath, S. S., Isaacs, N. J., Cvijanovic, N., Sun, E. W. L., Wu, T., et al. (2018) · International Journal of Obesity · doi:10.1038/s41366-018-0047-8 · Cited by 87
Metadata
- 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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