Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice
Open accessAbstract
The osteoblast-specific secreted molecule osteocalcin behaves as a hormone regulating glucose metabolism and fat mass in two mutant mouse strains. Here, we ask two questions: is the action of osteocalcin on β cells and adipocytes elicited by the same concentrations of the molecule, and more importantly, does osteocalcin regulate energy metabolism in WT mice? Cell-based assays using isolated pancreatic islets, a β cell line, and primary adipocytes showed that picomolar amounts of osteocalcin are sufficient to regulate the expression of the insulin genes and β cell proliferation markers, whereas nanomolar amounts affect adiponectin and Pgc1α expression in white and brown adipocytes, respectively. In vivo the same difference exists in osteocalcin's ability to regulate glucose metabolism on the one hand and affect insulin sensitivity and fat mass on the other hand. Furthermore, we show that long-term treatment of WT mice with osteocalcin can significantly weaken the deleterious effect on body mass and glucose metabolism of gold thioglucose-induced hyperphagia and high-fat diet. These results establish in WT mice the importance of this novel molecular player in the regulation of glucose metabolism and fat mass and suggest that osteocalcin may be of value in the treatment of metabolic diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
OCN may mediate its beneficial effects by stimulating the synthesis of adiponectin and IL-10, by decreasing TNF-α in adipocytes, and by upregulating thermogenic genes in AT and mitochondrial biogenesis in SkM.
“OCN may also mediate its beneficial effects by stimulating the synthesis of adiponectin [201,211] and IL-10, by decreasing TNF-α in adipocytes [211] and by upregulating thermogenic genes in AT [212] and mitochondrial biogenesis in SkM [213].”
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 [212]
In Results and Discussion (page unavailable), osteocalcin increased adiponectin gene expression in white adipocytes and white fat of wild-type mice, supporting the adiponectin part of the claim. The copy does not report increased IL-10 or decreased TNF-α in adipocytes. The thermogenic-gene and skeletal-muscle claims are attached to other citations in the citing sentence, so they are not assessed against this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOCN upregulates PGC-1α and UCP-1 in adipocytes.
“which in turn upregulates PGC-1α and UCP-1 in adipocytes [212].”
In adipose tissue, osteocalcin stimulates adiponectin gene expression, enhancing insulin sensitivity.
“In the adipose tissue, osteocalcin stimulates adiponectin gene expression that in turn enhances insulin sensitivity [204].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [204]
Undercarboxylated osteocalcin has lower affinity to minerals due to acidification during osteoclast resorption, and is carried by bloodstream to other organs.
“The undercarboxylated form shows lower affinity to minerals, due to acidification of bone matrix during osteoclast bone resorption, and then it is ferried by the bloodstream, reaching other organs [204, 205].”
From Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells (2015) · cites this paper as [204]
The livers of Osc-/- mice exhibit lipid accumulation and steatosis, and mice treated with OC exhibit no accumulation of lipids and normal liver morphology when fed a high-fat diet.
“It has been reported [86] that the livers of Osc-/Osc- mice exhibit lipid accumulation and steatosis, and mice treated with OC exhibit no accumulation of lipids and exhibit normal liver morphology when fed a high-fat diet [87,88].”
From Emerging role of liver-bone axis in osteoporosis (2024) · cites this paper as [86]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., et al. (2001) · Nature Medicine · doi:10.1038/90984 · Cited by 4,915 · see citing works
Endocrine regulation of energy metabolism by the skeleton
Lee, N. K., Sowa, H., Hinoi, E., Ferron, M., Ahn, J. D., Confavreux, C., Dacquin, R., Mee, P. J., McKee, M. D., Jung, D. Y., et al. (2007) · Cell · doi:10.1016/j.cell.2007.05.047 · Cited by 2,554 · see citing works
Self-citationIncreased bone formation in osteocalcin-deficient mice
Ducy, P. F., Morris, C., Boyce, B. F., Pinero, G. J., Story, B. M., Dunstan, C. R., Smith, E. A., Bonadio, J. F., Goldstein, S. A., Gundberg, C. M., et al. (1996) · Nature · doi:10.1038/382448a0 · Cited by 1,724 · see citing works
Self-citationDefective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase
Haemmerle, G., Lass, A., Zimmermann, R., Gorkiewicz, G., Meyer, C., Rozman, J., Heldmaier, G., Maier, R., Theussl, C., Eder, S., et al. (2006) · Science · doi:10.1126/science.1123965 · Cited by 1,375 · see citing works
Miyazaki, J., Araki, K., Yamato, E., Ikegami, H., Asano, T., Shibasaki, Y., Oka, Y., & Yamamura, K. (1990) · Endocrinology · doi:10.1210/endo-127-1-126 · Cited by 1,267 · see citing works
Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation
Kubota, N., Terauchi, Y., Yamauchi, T., Kubota, T., Moroi, M., Matsui, J., Eto, K., Yamashita, T., Kamon, J., Satoh, H., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200251200 · Cited by 1,213 · see citing works
Disruption of adiponectin causes insulin resistance and neointimal formation
Froguel, P. (2002) · HAL · Cited by 1,126 · see citing works
Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis
Yamauchi, T., Kamon, J., Waki, H., Imai, Y., Shimozawa, N., Hioki, K., Uchida, S., Ito, Y., Takakuwa, K., Matsui, J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209033200 · Cited by 911 · see citing works
Rane, S. G., Dubus, P., Mettus, R. V., Galbreath, E. J., Boden, G., Reddy, E. P., & Barbacid, M. (1999) · Nature Genetics · doi:10.1038/8751 · Cited by 700 · see citing works
Uldry, M., Yang, W., St‐Pierre, J., Lin, J. D., Seale, P., & Spiegelman, B. M. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.002 · Cited by 644 · see citing works
Tam, C. S., Heersche, J. N. M., Murray, T. M., & PARSONS, J. A. (1982) · Endocrinology · doi:10.1210/endo-110-2-506 · Cited by 611 · see citing works
Absence of perilipin results in leanness and reverses obesity in Leprdb/db mice
Martı́nez-Botas, J., Anderson, J. B., Tessier, D., Lapillonne, A., Chang, B. H., Quast, M. J., Gorenstein, D. G., Chen, K.-H., & Chan, L. (2000) · Nature Genetics · doi:10.1038/82630 · Cited by 580 · see citing works
Yoon, M. J., Lee, G. Y., Chung, J.-J., Ahn, Y. H., Hong, S. H., & Kim, J. B. (2006) · Diabetes · doi:10.2337/db05-1322 · Cited by 546 · see citing works
Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo
Bogacka, I., Xie, H., Bray, G. A., & Smith, S. R. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1392 · Cited by 467 · see citing works
Cyclins D2 and D1 Are Essential for Postnatal Pancreatic β-Cell Growth
Kushner, J. A., Ciemerych, M. A., Sicinska, E., Wartschow, L. M., Teta, M., Long, S. Y., Sicinski, P., & White, M. F. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.9.3752-3762.2005 · Cited by 334 · see citing works
Variation in Type 2 Diabetes-Related Traits in Mouse Strains Susceptible to Diet-Induced Obesity
Rossmeisl, M., Rim, J. S., Koza, R. A., & Kozak, L. P. (2003) · Diabetes · doi:10.2337/diabetes.52.8.1958 · Cited by 283 · see citing works
Phenotypic alterations in insulin-deficient mutant mice
Duvillié, B., Cordonnier, N., Deltour, L., Dandoy‐Dron, F., Itier, J., Monthioux, E., Jami, J., Joshi, R. L., & Bucchini, D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5137 · Cited by 272 · see citing works
Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes
Faßhauer, M., Klein, J. C., Kriauciunas, K. M., Ueki, K., Benito, M., & Kahn, C. R. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.1.319-329.2001 · Cited by 171 · see citing works
Continuous Subcutaneous Infusion of Insulin in the Management of Diabetes Mellitus
Champion, M. C., Shepherd, G. A. A., Rodger, N. W., et al. (1980) · Diabetes · doi:10.2337/diab.29.3.206 · Cited by 117 · see citing works
Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Gene-Targeted Mice
Tolwani, R. J., Hamm, D. A., Tian, L., Sharer, J. D., Vockley, J. E., Rinaldo, P., Matern, D., Schoeb, T. R., & Wood, P. A. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010023 · Cited by 112 · see citing works
Perforin and Fas induced by IFNγ and TNFα mediate beta cell death by OT-I CTL
McKenzie, M. D., Dudek, N. L., Mariana, L., et al. (2006) · International Immunology · doi:10.1093/intimm/dxl020 · Cited by 70 · see citing works
THE BRAIN LESION OF GOLDTHIOGLUCOSE OBESITY
Brecher, G., Laqueur, G. L., Cronkite, E. P., Edelman, P. M., & Schwartz, I. L. (1965) · The Journal of Experimental Medicine · doi:10.1084/jem.121.3.395 · Cited by 52 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells
Florencio-Silva, R., Sasso, G. R. D. S., Sasso-Cerri, E., Simões, M. J., & Cerri, P. S. (2015) · BioMed Research International · doi:10.1155/2015/421746 · Cited by 2,044 · see citing works
Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism
Ferron, M., Wei, J., Yoshizawa, T., Del Fattore, A., DePinho, R. A., Teti, A., Ducy, P., & Karsenty, G. (2010) · Cell · doi:10.1016/j.cell.2010.06.003 · Cited by 1,123 · see citing works
Endocrine Regulation of Male Fertility by the Skeleton
Oury, F., Sumara, G., Sumara, O., Ferron, M., Chang, H., Smith, C. E., Hermo, L., Suarez, S., Roth, B. L., Ducy, P., et al. (2011) · Cell · doi:10.1016/j.cell.2011.02.004 · Cited by 628 · see citing works
Self-citationThe contribution of bone to whole-organism physiology
Karsenty, G., & Ferron, M. (2012) · Nature · doi:10.1038/nature10763 · Cited by 537 · see citing works
Self-citationOsteoblast and osteocyte: Games without frontiers
Capulli, M., Paone, R., & Rucci, N. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.05.003 · Cited by 413 · see citing works
Ferron, M., McKee, M. D., Levine, R. L., Ducy, P., & Karsenty, G. (2012) · Bone · doi:10.1016/j.bone.2011.04.017 · Cited by 414 · see citing works
Osteocalcin: Skeletal and extra‐skeletal effects
Neve, A., Corrado, A., & Cantatore, F. P. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24278 · Cited by 335 · see citing works
Fukumoto, S., & Martin, T. J. (2009) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2009.02.001 · Cited by 311 · see citing works
The role of osteoblasts in energy homeostasis
Dirckx, N., Moorer, M. C., Clemens, T. L., & Riddle, R. C. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0246-y · Cited by 292 · see citing works
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
The diverse metabolic roles of peripheral serotonin
Martin, A. M., Young, R. L., Leong, L., Rogers, G. B., Spencer, N. J., Jessup, C. F., & Keating, D. J. (2017) · Endocrinology · doi:10.1210/en.2016-1839 · Cited by 261 · see citing works
Hou, Y.-F., Shan, C., Zhuang, S.-Y., Zhuang, Q.-Q., Ghosh, A., Zhu, K.-C., Kong, X.-K., Wang, S.-M., Gong, Y.-L., Yang, Y.-Y., et al. (2021) · Microbiome · doi:10.1186/s40168-020-00988-6 · Cited by 231 · see citing works
Rafacho, A., Ortsäter, H., Nadal, A., & Quesada, I. (2014) · Journal of Endocrinology · doi:10.1530/joe-14-0373 · Cited by 216 · see citing works
Hwang, Y., Jeong, I., Ahn, K. J., & Chung, H. Y. (2009) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1045 · Cited by 214 · see citing works
Regulation of energy metabolism by the skeleton: osteocalcin and beyond
Ferron, M., & Lacombe, J. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.05.022 · Cited by 211 · see citing works
Cohen, A., Dempster, D. W., Recker, R. R., Lappe, J. M., Zhou, H., Zwahlen, A., Müller, R., Zhao, B., Guo, X., Lang, T., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1047 · Cited by 206 · see citing works
Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway
Rowe, P. S. N. (2012) · Critical Reviews™ in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v22.i1.50 · Cited by 173 · see citing works
Effect of Vitamin K Supplementation on Insulin Resistance in Older Men and Women
Yoshida, M., Jacques, P. F., Meigs, J. B., Saltzman, E., Shea, M. K., Gundberg, C., Dawson-Hughes, B., Dallal, G., & Booth, S. L. (2008) · Diabetes Care · doi:10.2337/dc08-1204 · Cited by 177 · see citing works
Glucocorticoids and bone: Local effects and systemic implications
Henneicke, H., Gasparini, S. J., Brennan-Speranza, T. C., Zhou, H., & Seibel, M. J. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.12.006 · Cited by 168 · see citing works
Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states
El Ouaamari, A., Kawamori, D., Dirice, E., Liew, C. W., Shadrach, J. L., Hu, J., Katsuta, H., Hollister-Lock, J., Qian, W.-J., Wagers, A. J., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.007 · Cited by 136 · see citing works
Bariatric 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 · see citing works
Inverse relationship between serum osteocalcin levels and visceral fat area in Chinese men
Bao, Y., Ma, X., Yang, R., Wang, F., Hao, Y., Dou, J., He, H., & Jia, W. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2906 · Cited by 116 · see citing works
Bone: from a reservoir of minerals to a regulator of energy metabolism
Confavreux, C. B. (2011) · Kidney International · doi:10.1038/ki.2011.25 · Cited by 113 · see citing works
Choi, H. J., Yu, J., Choi, H., An, J. H., Kim, S. W., Park, K. S., Jang, H. C., Kim, S. Y., & Shin, C. S. (2011) · Diabetes Care · doi:10.2337/dc11-0551 · Cited by 106 · see citing works
Regulation of Energy Metabolism by Bone-Derived Hormones
Mera, P., Ferron, M., & Mosialou, I. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031666 · Cited by 90 · see citing works
Self-citationZhou, B., Li, H., Xu, L., Zang, W., Wu, S., & Sun, H. (2013) · Endocrinology · doi:10.1210/en.2012-2144 · Cited by 86 · see citing works
Shi, T., Shen, S., Shi, Y., Wang, Q., Zhang, G., Lin, J., Chen, J., Bai, F., Zhang, L., Wang, Y., et al. (2024) · Nature Metabolism · doi:10.1038/s42255-024-00989-x · Cited by 87 · see citing works
Hill, H., Grams, J., Walton, R., Liu, J., Moellering, D., & Garvey, W. (2014) · Hormone and Metabolic Research · doi:10.1055/s-0034-1368709 · Cited by 80 · see citing works
Nohara, K., Waraich, R. S., Liu, S., Ferron, M., Waget, A., Meyers, M. S., Karsenty, G., Burcelin, R., & Mauvais-Jarvis, F. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00620.2012 · Cited by 77 · see citing works
Self-citationOsteocalcin effect on human β-cells mass and function
Sabek, O. M., Nishimoto, S. K., Fraga, D., Tejpal, N., Ricordi, C., & Gaber, A. O. (2015) · Endocrinology · doi:10.1210/en.2015-1143 · Cited by 74 · see citing works
Osteocalcin: an osteoblast-derived polypeptide hormone that modulates whole body energy metabolism
Brennan-Speranza, T. C., & Conigrave, A. D. (2015) · Calcified Tissue International · doi:10.1007/s00223-014-9931-y · Cited by 71 · see citing works
Cheng, Y., Zhang, Q., Meng, Q., Xia, T., Huang, Z., Wang, C., Liu, B., Chen, S., Xiao, F., Du, Y., et al. (2011) · Molecular Endocrinology · doi:10.1210/me.2011-0028 · Cited by 65 · see citing works
Glucose Metabolism in Osteoblasts in Healthy and Pathophysiological Conditions
Donat, A., Knapstein, P.-R., Jiang, S., Baranowsky, A., Ballhause, T.-M., Frosch, K.-H., & Keller, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22084120 · Cited by 53 · see citing works
Shan, C., Zhang, D., Ma, D.-N., Hou, Y.-F., Zhuang, Q.-Q., Gong, Y.-L., Sun, L.-H., Zhao, H.-Y., Tao, B., Yang, Y.-Y., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01343-y · Cited by 53 · see citing works
Bone circuitry and interorgan skeletal crosstalk
Zaidi, M., Kim, S.-M., Mathew, M., Korkmaz, F., Sultana, F., Miyashita, S., Gumerova, A. A., Frolinger, T., Moldavski, O., Barak, O., et al. (2023) · eLife · doi:10.7554/elife.83142 · Cited by 45 · see citing works
Association between serum osteocalcin and body mass index: A systematic review and meta-analysis
Kord-Varkaneh, H., Djafarian, K., khorshidi, M., & Shab-Bidar, S. (2017) · Endocrine · doi:10.1007/s12020-017-1384-4 · Cited by 43 · see citing works
Shea, M. K., Dawson-Hughes, B., Gundberg, C. M., & Booth, S. L. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2989 · Cited by 31 · see citing works
Emerging role of liver-bone axis in osteoporosis
Gao, H., Peng, X., Li, N., Gou, L., Xu, T., Wang, Y., Qin, J., Liang, H., Ma, P., Li, S., et al. (2024) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2024.07.008 · Cited by 36 · see citing works
Fatahi, S., Ghaedi, E., Mousavi, S. M., Bawadi, H., Rahmani, J., Pezeshki, M., & Varkaneh, H. K. (2019) · Hormone and Metabolic Research · doi:10.1055/a-0897-844 · Cited by 6 · see citing works
- Authors
- Ferron, M., Hinoi, E., Karsenty, G., & Ducy, P.
- Affiliations
- Columbia University (US)
- Departments of *Genetics and Development and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-04
- Volume
- 105
- Issue
- 13
- Pages
- 5266-5270
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2278202
- OpenAlex
- W2047761422
- Cited by
- 900
- References
- 22
- Citations by year
- 2026: 18 · 2025: 9 · 2024: 39 · 2023: 21 · 2022: 37 · 2021: 41 · 2020: 56 · 2019: 47 · 2018: 38 · 2017: 69 · 2016: 51 · 2015: 70 · 2014: 68 · 2013: 72 · 2012: 72
- FWCI
- 25.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- osteocalcin, pancreatic beta cells, adipocytes, insulin gene expression, beta-cell proliferation, adiponectin, PGC-1α, glucose metabolism, insulin sensitivity, fat mass, hyperphagia, high-fat diet, metabolic disorders, pancreatic islets, brown adipose tissue
- MeSH terms
- Insulin Secretion, Adipose Tissue, Animals, Cells, Cultured, Diabetes Mellitus, Female, Gene Expression Regulation, Glucose, Insulin, Metabolic Diseases, Mice, Inbred C57BL, Obesity, Sensitivity and Specificity, Osteocalcin, Adipocytes, Insulin-Secreting Cells, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
