Regulation of Energy Metabolism by Bone-Derived Hormones
Open accessAbstract
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or "osteokines." At least two osteokines are implicated in the control of glucose and energy metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signaling in the brain. This action of LCN2 occurs through its binding to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) and ventromedial neurons of the hypothalamus.
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Osteocalcin is released by bone following bouts of exercise and cooperates with myokines to increase free fatty acid utilization in multiple tissues.
“the osteokine osteocalcin (OCN) is released by bone following bouts of exercise and cooperates with myokines to increase FFA utilization in multiple tissues [28]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [28]
The exercise and skeletal-muscle sections report that bioactive osteocalcin rises after exercise and promotes fatty-acid utilization in muscle. The cross-talk section describes an interaction with the myokine IL-6, but says whether they act synergistically to increase fatty-acid utilization remains to be established. It does not report increased fatty-acid utilization in multiple tissues; it describes fatty-acid production in white adipose tissue instead. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOCN is known to increase with acute bouts of exercise, such as 4 × 4-min cycling at 95% maximum heart rate HIIT.
“Importantly, OCN is known to increase with acute bouts of exercise, such as 4 × 4-min cycling at 95% maximum heart rate HIIT [28,214].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [28]
The section “A Role for Osteocalcin in Adaptation to Exercise” (page unavailable) says circulating bioactive OCN doubles after a single bout of endurance exercise in mice and humans. It does not describe the cited example of 4 × 4-minute cycling at 95% maximum heart rate, so the specific HIIT protocol is not supported by this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIL-6 increases production of OCN by osteoblasts, which itself stimulates transient pancreatic secretion of the anorexic hormone insulin and triggers a positive feed-forward mechanism that results in increased OCN and thus more insulin.
“Moreover, IL-6 increases production of OCN by osteoblasts [71] (2c), which itself stimulates transient pancreatic secretion of the anorexic hormone insulin and triggers a positive feed-forward mechanism that results in increased OCN and thus more insulin [28,209,210] (2d).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [28]
The cross-talk section (page unavailable) says IL-6 increases bioactive osteocalcin during exercise, while the glucose-metabolism section says osteocalcin stimulates pancreatic insulin secretion. The bone-resorption section describes a feed-forward loop in which insulin signaling increases the release of bioactive osteocalcin. It does not say that IL-6 directly increases osteocalcin production by osteoblasts, or characterize insulin here as an anorexic hormone. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOCN and irisin may exert direct anti-oxidant and anti-inflammatory effects in the liver.
“OCN [28,215] and irisin [61,65], on the other hand, may also exert direct anti-oxidant and anti-inflammatory effects in the liver.”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [28]
The OCN section’s Figure 1 caption says osteocalcin may decrease inflammation in steatotic liver, supporting a possible anti-inflammatory effect. It does not describe an antioxidant effect or establish that the liver effect is direct. This paper is cited for OCN, not irisin; the indexed passages provide no page number. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOsteocalcin (OCN) is a bone-derived hormone that is synthesized and secreted by osteoblasts and then activated by osteoclasts during the process of bone resorption.
“Osteocalcin (OCN) is a bone-derived hormone that is synthesized and secreted by osteoblasts and then activated by osteoclasts during the process of bone resorption [28].”
Osteokines are essential for regulating the expression of PGC-1α, improving insulin sensitivity, and promoting mitochondria biogenesis in skeletal muscle.
“Osteokines are essential for regulating the expression of PGC-1α, improving insulin sensitivity, and promoting mitochondria biogenesis in skeletal muscle [134].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [134]
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“LCN2 Study of the endocrine functions of OCN in the regulation of energy metabolism posed a question as whether additional bonederived hormones existed which could affect energy metabolism.(139) Food intake increased in mice that had undergone osteoblast ablation while additional administration of OCN did not further…”
BackgroundThe role of osteoblasts in energy homeostasis
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The Interplay Between Bone and Glucose Metabolism
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“Few experimental studies showed the possible involvement of the receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), lipocalin-2 (LCN2), and periostin in these pathways (30, 31).”
BackgroundThe Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases
Popa, D., Bigman, G., & Rusu, M. E. (2021) · Antioxidants · doi:10.3390/antiox10040566 · Cited by 129 · see citing works
“In animal studies, ucOC was found to be the active hormonal form that conferred beneficial glucose control and the only molecule involved in the production of insulin by the pancreatic β-cells [154].”
BackgroundOsteocalcin promotes bone mineralization but is not a hormone
Manolagas, S. C. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008714 · Cited by 117 · see citing works
Lipocalin-2 counteracts metabolic dysregulation in obesity and diabetes
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“The discovery of the multiple endocrine functions of bone established a new paradigm whereby bone is a regulator of energy metabolism (Mera et al., 2018; Liu et al., 2018; Lee et al., 2007; Mera et al., 2016; Wei et al., 2014; Ferron et al., 2010; Yoshikawa et al., 2011).”
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Blood Vessels and Vascular Niches in Bone Development and Physiological Remodeling
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“Importance of bone-derived factors such as osteocalcin and Lipocalin-2 in the regulation of systemic functions has been an intensive field of research (Mera et al., 2018; Chen et al., 2020).”
BackgroundThe Regulation of Peripheral Metabolism by Gut-Derived Hormones
Sun, E. W. L., Martin, A. M., Young, R. L., & Keating, D. J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00754 · Cited by 71 · see citing works
“Such observation could be attributed to the anti-apoptotic effect of GIP on osteoblasts (71), as osteoblast-derived hormones such as osteocalcin and lipocalcin 2 are implicated in regulating peripheral metabolism and modulate food intake (36, 72).”
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Role of Physical Activity in Bone–Muscle Crosstalk: Biological Aspects and Clinical Implications
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Bone-Muscle Mutual Interactions
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Crosstalk Between the Neuroendocrine System and Bone Homeostasis
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Brain to bone: What is the contribution of the brain to skeletal homeostasis?
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Bone-organ axes: bidirectional crosstalk
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“This interaction plays a crucial role in mediating the anorexia pathway and regulating energy metabolism [62, 63].”
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Emerging and Established Models of Bone Metastasis
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“In particular, the effects that bone-specific hormones have on the global physiology are not taken into account [108].”
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“Bone is now regarded as an endocrine organ modulating whole-body energy metabolism through secreting several osteokines; OCN is the most important one among them (Mera et al., 2017), and its role in brain was recently identified and thus opened a new field in this area (Oury et al.”
BackgroundBone: Another potential target to treat, prevent and predict diabetes
Liu, D., Mosialou, I., & Liu, J. (2018) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13330 · Cited by 45 · see citing works
“Putting all these pieces together, it is tempting to speculate that the elevation in LCN2 during unloading may serve to preserve homeostasis, matching feeding to energy demands.(85) Nevertheless, how osteoblasts can sense gravitational forces and what triggers LCN2 release remain unknown.”
BackgroundSelf-citationLacombe, J., Rifai, O. A., Loter, L., Moran, T. M., Turcotte, A., Grenier–Larouche, T., Tchernof, A., Biertho, L. D., Carpentier, A. C., Prud’homme, D., et al. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00321.2019 · Cited by 42 · see citing works
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“Although other lipocalins have been indicated in appetite regulation [64,65], this has not been described for A1M and may open up new areas within A1M research.”
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“blood-brain barrier and act directly on anorexigenic melanocortin receptors with similar affinity to a-MSH (Mera et al., 2018).”
BackgroundPharmacology and physiological function of the orphan GPRC6A receptor
Jørgensen, C. V., & Bräuner‐Osborne, H. (2020) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/bcpt.13397 · Cited by 29 · see citing works
The role of bone in energy metabolism: A focus on osteocalcin
Smith, C., Lin, X., Parker, L., Yeap, B. B., Hayes, A., & Levinger, I. (2024) · Bone · doi:10.1016/j.bone.2024.117238 · Cited by 32 · see citing works
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“In addition to its role in bone mineralization, osteocalcin is important in free fatty acid and glucose uptake [61] and mitochondrial biogenesis and insulin sensitivity [62] in skeletal muscle.”
BackgroundCirculating levels of lipocalin-2 are associated with fatty pancreas but not fatty liver
Singh, R. G., Nguyen, N. N., Cervantes, A., Kim, J. U., Stuart, C. E., & Petrov, M. S. (2019) · Peptides · doi:10.1016/j.peptides.2019.170117 · Cited by 25 · see citing works
Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis
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The central melanocortin system as a treatment target for obesity and diabetes: A brief overview
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Sarcopenia and bone health: new acquisitions for a firm liaison
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Recent advances in the crosstalk between adipose, muscle and bone tissues in fish
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Bone Regulation of Insulin Secretion and Glucose Homeostasis
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Protective role of osteocalcin in diabetes pathogenesis
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Increased lipocalin 2 levels in adolescents with type 2 diabetes mellitus
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The bone hormones and their potential effects on glucose and energy metabolism
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“Recent studies have shown that at least two bone-derived hormones are implicated in the control of glucose and energy metabolism, namely osteocalcin (OCN) and lipocalin-2 (LCN2) (Mera et al. 2018).”
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“calcin, a molecule that stimulates insulin secretion from pancreatic b cells as well as glucose and fatty acid metabolism in muscle.(14) Lastly, for those with higher spinal injury levels, it has been suggested that,”
Artamonov, M. Y., Sokov, E. L., Kornilova, L. E., & Minenko, I. A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26083876 · Cited by 6 · see citing works
“Osteocalcin plays a role in regulating insulin secretion and sensitivity, while lipocalin-2 influences appetite control by acting on the brain [45].”
Tauer, J. T., Boraschi-Diaz, I., Rifai, O. A., Rauch, F., Ferron, M., & Komarova, S. V. (2021) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2021.03.014 · Cited by 6 · see citing works
Self-citationPan-Cancer Analyses Reveal Prognostic Value of Osteomimicry Across 20 Solid Cancer Types
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The Role of Osteocalcin in Placental Function in Gestational Diabetes Mellitus
Song, L., Huang, Y., Long, J., Li, Y., Pan, Z., Fang, F., Yu, L., Huang, C., Qi, N., Guo, Y., et al. (2021) · Reproductive Biology · doi:10.1016/j.repbio.2021.100566 · Cited by 5 · see citing works
The Protective Role of Vitamin K in Aging and Age-Related Diseases
Kaźmierczak-Barańska, J., & Karwowski, B. T. (2024) · Nutrients · doi:10.3390/nu16244341 · Cited by 5 · see citing works
“Studies a bioactive form of the protein [44].”
Turcotte, A., Grenier–Larouche, T., Lacombe, J., Carreau, A., Carpentier, A. C., Mac‐Way, F., Tchernof, A., Richard, D., Biertho, L. D., Lebel, S., et al. (2020) · Endocrine · doi:10.1007/s12020-020-02340-2 · Cited by 5 · see citing works
Self-citationMaternal adaptations of the pancreas and glucose homeostasis in lactation and after lactation
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Bone as an endocrine regulator of lipid and energy metabolism
Liu, H., Zhao, J., Liu, L., Ying, W., Liu, S., Luo, E., & Rosen, C. J. (2026) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-026-10052-7 · Cited by 4 · see citing works
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Role of osteokines in atherosclerosis
Liu, Y., Tian, Y., Chen, X., Zhang, C., & Huang, L. (2024) · Cell Biochemistry and Function · doi:10.1002/cbf.4107 · Cited by 3 · see citing works
“7 It predominantly exists as undercarboxylated osteocalcin (UcOCN) and carboxylated osteocalcin (cOCN), each possessing distinct functionalities 8 ; while cOCN is deposited within the mineralized bone matrix, UcOCN is released into the bloodstream where it acts as a hormone to regulate various…”
Osteocalcin: A new phenomenon for type 2 diabetes and obesity
Koçak, T., & Tek, N. A. (2023) · European Journal of Environment and Public Health · doi:10.29333/ejeph/12799 · Cited by 3 · see citing works
The Role of Non-collagenous Proteins and Other Matrix Molecules in Vertebrate Mineralization
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“36 Also, the positive correlation between lipocalin-2 CRP and ESR is attributed to the fact that they are considered important inflammatory indicators, and their production is stimulated by pro-inflammatory cytokines that play an important role in causing arthritis.”
BackgroundYin, M., Shi, H., Lv, C., Shi, L., Xie, L., Yu, G., & Xu, K. (2025) · Medicine Plus · doi:10.1016/j.medp.2025.100104 · Cited by 2 · see citing works
Vitamin K as an Endocrine Modulator: Mechanistic Links to Glucose Metabolism and Beyond
Matuszewski, W., Madeksza, M., Szklarz, M., Rutkiewicz, A., Rutkowska, J., & Harazny, J. M. (2026) · Nutrients · doi:10.3390/nu18081183 · Cited by 2 · see citing works
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“A direct effect of OCN as an insulin-sensitizing hormone is speculative and requires further evaluation (20).”
BackgroundKumar, V., Bolanthakodi, N., Vidyasagar, S., Holla, A., Sheik, S. M., & Abhishek, S. (2022) · International Journal of Diabetes in Developing Countries · doi:10.1007/s13410-022-01087-y · Cited by 1 · see citing works
“” The first such osteokine recognized to link bone and glucose metabolism is osteocalcin (OC), which functions in its active form, that is, undercarboxylated OC (ucOC) [1].”
BackgroundFakhrealali, M., Hejazi, K., & Marafeti, H. (2024) · Jentashapir Journal of Cellular and Molecular Biology · doi:10.5812/jjcmb-157664 · Cited by 1 · see citing works
“Furthermore, OC production by osteoblasts and its activation by bone resorption are increased (25).”
Kim, K. J., Jang, S. A., Kwon, S., Seo, G. H., & Kim, K. M. (2025) · Calcified Tissue International · doi:10.1007/s00223-025-01385-7 · Cited by 1 · see citing works
“The bone is not just a structural organ but also plays a role in regulating energy metabolism [14, 15].”
Two decades into the crosstalk between bone and energy metabolism
Ducy, P. F. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01179-9 · Cited by 1 · see citing works
Circulating Molecular Drivers of Bone Remodeling in Pancreatitis
Hill, R. L., Yadav, D., Hart, P. A., Whitcomb, D. C., McQuerry, K., Karnik, K. N., Stello, K. M., Conwell, D. L., & Rao, M. (2025) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000926 · Cited by 1 · see citing works
“In this way, insulin contributes to both bone formation and resorption, linking skeletal remodeling to glucose homeostasis (48,49).”
Lipocalin-2 upregulation in hypoxic murine osteocytes enhances RANKL-induced osteoclastogenesis
Narita, K., Ohori, F., Marahleh, A., Ma, J., Ren, J., Lin, A., Fan, Z., Murakami, K., & Kitaura, H. (2026) · Scientific Reports · doi:10.1038/s41598-025-34575-2 · Cited by 1 · see citing works
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Association of serum osteocalcin levels with glucose metabolism in trauma patients
Yang, Y., Zhong, W., Huang, J., Geng, L., & Feng, Q. (2020) · Medicine · doi:10.1097/md.0000000000021901 · Cited by 1 · see citing works
“Bone regulates glucose metabolism via OC.([14,15]) Numerous clinical studies have investigated the relationships between serum OC levels and glucose metabolism indicators in healthy as well as disease conditions, but the conclusions have been inconsistent regarding the association of OC with blood glucose, insulin, an…”
ResultInfluentialÚj szemléletmód a renalis osteodystrophia diagnosztikájában és kezelésében
Mácsai, E., Szlovák, E., & Dolgos, S. (2021) · Hypertonia és Nephrologia · doi:10.33668/hn.25.012
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The Effect of Osteocalcin in Middle-Age Women With and Without Type2 Diabetes Mellitus
Jassim, H. I., & Hussein, A. L. (2024) · Diyala Journal of Medicine · doi:10.26505/djm.v27i2.1224
Osteocalcin and metabolic syndrome
Consolim‐Colombo, F. M., & Lopes, H. F. (2025) · Scripta Medica · doi:10.5937/scriptamed56-59319
Osteocalcin has many tricks to get γ-carboxylated
Ferron, M. (2025) · Cell Research · doi:10.1038/s41422-025-01177-6
Self-citationA systematic analysis of human hormone receptors
Zhao, X., & Wang, X. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2950-4
Endocrine Functions of Bone Are Suppressed by Orally Administered Glucose Regardless of Bodyweight
Jalava, N., Heino, T. J., Nuutila, P., Virtanen, K. A., & Ivaska, K. K. (2025) · Clinical Endocrinology · doi:10.1111/cen.70059
Bergsport und Stütz- und Bewegungsapparat
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Laboratory markers of bone metabolism in relation to adaptive reserves and musculoskeletal disorders
Александровна, А. Н., Алексеевна, К. Н., Aleksanin, S. S., Rybnikov, V. Y., & Magdanov, D. F. (2025) · Экология человека · doi:10.17816/humeco680144
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“For instance, the acidic microenvironment generated during osteoclastic bone resorption facilitates the decarboxylation of OCN, converting it from the carboxylated matrix-bound form (Gla-OCN) to the under-carboxylated endocrine-active form (Glu-OCN) that enters the circulation [72,73].”
Gaio, P. D. C., Lizana, R. R., Custódio, D. K., Cheneri, C. K., Messias, R. K. G., Leme, B. B., & Sakomura, N. K. (2026) · Animal Feed Science and Technology · doi:10.1016/j.anifeedsci.2026.117027
Role of Osteocalcin in the Regulation of Glucose Metabolism in Children and Adolescents with Obesity
Sbilordo, S., Drago, S. F. A., Catalano, A., Zirilli, G., Salzano, G., Lombardo, F., Passanisi, S., Bombaci, B., Grasso, L., Aguennouz, M., et al. (2026) · Nutrients · doi:10.3390/nu18203418
“It also stimulates the release of cytokines, most notably interleukin-6 (IL-6), which contributes to the regulation of hepatic gluconeogenesis and promotes fatty acid mobilization from adipose tissue [12,27].”
- Authors
- Mera, P., Ferron, M., & Mosialou, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- Montreal Clinical Research Institute (CA)
- Venue
- Cold Spring Harbor Perspectives in Medicine
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-08-04
- Volume
- 8
- Issue
- 6
- Pages
- a031666
- ISSN
- 2157-1422 (ISSN-L)
- PMC
- PMC5983159
- OpenAlex
- W2744690554
- Cited by
- 90
- References
- 91
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 12 · 2020: 22 · 2019: 5 · 2018: 6
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP133652)
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- osteokines, bone endocrine function, osteocalcin, neutrophil gelatinase-associated lipocalin, energy metabolism, glucose metabolism, insulin secretion, GPRC6A, exercise adaptation, fatty acid utilization, melanocortin-4 receptor, hypothalamic regulation of appetite, paraventricular nucleus
- MeSH terms
- Lipocalin-2, Animals, Bone and Bones, Energy Metabolism, Glucose, Humans, Insulin, Signal Transduction, Exercise, Osteocalcin, Receptors, G-Protein-Coupled, Receptor, Melanocortin, Type 4
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