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Gerard Karsenty - One of the best experts on this subject based on the ideXlab platform.
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Osteocalcin in the brain: from embryonic development to age-related decline in cognition
Nature Reviews Endocrinology, 2018Co-Authors: Arnaud Obri, Gerard Karsenty, Lori Khrimian, Franck OuryAbstract:A remarkable, unexpected aspect of the bone-derived hormone Osteocalcin is that it is necessary for both brain development and brain function in the mouse, as its absence results in a profound deficit in spatial learning and memory and an exacerbation of anxiety-like behaviour. The regulation of cognitive function by Osteocalcin, together with the fact that its circulating levels decrease in midlife compared with adolescence in all species tested, raised the prospect that Osteocalcin might be an anti-geronic hormone that could prevent age-related cognitive decline. As presented in this Review, recent data indicate that this is indeed the case and that Osteocalcin is necessary for the anti-geronic activity recently ascribed to the plasma of young wild-type mice. The diversity and amplitude of the functions of Osteocalcin in the brain, during development and postnatally, had long called for the identification of its receptor in the brain, which was also recently achieved. This Review presents our current understanding of the biology of Osteocalcin in the brain, highlighting the bony vertebrate specificity of the regulation of cognitive function and pointing toward where therapeutic opportunities might exist. The bone-derived hormone Osteocalcin is not only involved with energy metabolism but is also necessary for brain development and function in mice. This Review discusses the role of Osteocalcin in the regulation of cognitive function in the mouse brain and potential therapeutic opportunities. Undercarboxylated Osteocalcin regulates anxiety and cognition in adult mice Osteocalcin is necessary and sufficient to correct age-related decline in cognitive function in mice Mouse maternal Osteocalcin contributes to brain development and the acquisition of cognitive function in the fetus starting at embryonic day (E) 14.5 Probable G protein-coupled receptor 158 (GPR158) regulates the role of Osteocalcin in anxiety and cognition in the mouse brain
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Osteocalcin is necessary and sufficient to maintain muscle mass in older mice
Molecular metabolism, 2016Co-Authors: Paula Mera, Kathrin Laue, Jianwen Wei, Julian Meyer Berger, Gerard KarsentyAbstract:Abstract Objective A decrease in muscle protein turnover and therefore in muscle mass is a hallmark of aging. Because the circulating levels of the bone-derived hormone Osteocalcin decline steeply during aging in mice, monkeys and humans we asked here whether this hormone might regulate muscle mass as mice age. Methods We examined muscle mass and strength in mice lacking Osteocalcin ( Ocn −/−) or its receptor in all cells ( Gprc6a −/−) or specifically in myofibers ( Gprc6a Mck −/−) as well as in 9 month-old WT mice receiving exogenous Osteocalcin for 28 days. We also examined protein synthesis in WT and Gprc6a −/− mouse myotubes treated with Osteocalcin. Results We show that Osteocalcin signaling in myofibers is necessary to maintain muscle mass in older mice in part because it promotes protein synthesis in myotubes without affecting protein breakdown. We further show that treatment with exogenous Osteocalcin for 28 days is sufficient to increase muscle mass of 9-month-old WT mice. Conclusion This study uncovers that Osteocalcin is necessary and sufficient to prevent age-related muscle loss in mice.
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In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice
Molecular metabolism, 2013Co-Authors: Julie Lacombe, Gerard Karsenty, Mathieu FerronAbstract:Osteocalcin is a hormone produced in bones by osteoblasts and regulating energy metabolism. While Osteocalcin exists in two forms, γ-carboxylated and undercarboxylated only the latter appears to function as a hormone in vivo. It has been proposed recently that osteoclasts, the bone-resorbing cells, are responsible of decarboxylating, i.e. activating Osteocalcin. To address the role of osteoclasts in the maintenance of energy metabolism we analyzed mutant mouse strains harboring either an increase or a decrease in osteoclasts number. Osteoprotegerin-deficient mice that are characterized by an increase in the number of osteoclasts demonstrate an increase in serum levels of undercarboxylated Osteocalcin and are significantly more glucose tolerant than WT animals. Conversely, osteoclasts ablation in mice results in a decrease in serum undercarboxylated Osteocalcin levels and in reduced glucose tolerance. These results support the notion that osteoclasts are controlling glucose metabolism at least in part through the regulation of Osteocalcin decarboxylation.
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intermittent injections of Osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice
Bone, 2012Co-Authors: Mathieu Ferron, Patricia Ducy, Marc D Mckee, Robert L Levine, Gerard KarsentyAbstract:The uncarboxylated form of the osteoblast-specific secreted molecule Osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of Osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated Osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of Osteocalcin. We found that daily injections of Osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both β-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of Osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent Osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving Osteocalcin daily. Overall, these results provide evidence that daily injections of Osteocalcin can improve glucose handling and prevent the development of type 2 diabetes.
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An ELISA-based method to quantify Osteocalcin carboxylation in mice.
Biochemical and biophysical research communications, 2010Co-Authors: Mathieu Ferron, Jianwen Wei, Tatsuya Yoshizawa, Patricia Ducy, Gerard KarsentyAbstract:Osteocalcin was recently identified as an osteoblast-secreted hormone regulating insulin secretion and sensitivity. In mice and humans, Osteocalcin can be present in the serum in carboxylated or undercarboxylated forms and it has been shown that it is the undercarboxylated form of Osteocalcin which acts as a hormone. The study of Osteocalcin different circulating forms in mouse serum, however, has been hampered by the absence of quantitative methodology. Here we described a triple enzyme-linked immunosorbent assay (ELISA) system for quantification of mouse total, carboxylated and uncarboxylated Osteocalcin. That carboxylation of Osteocalcin was decreased in mouse osteoblasts cultures treated with warfarin, an inhibitor of carboxylation validated this assay. This ELISA could also detect elevated levels of undercarboxylated Osteocalcin in the serum of mice treated with warfarin and in the serum of Esp -/- mice, a mouse model known to have more undercarboxylated, i.e., active Osteocalcin. These results show that this new ELISA system is a reliable method to assess carboxylation status of Osteocalcin in cell culture supernatants as well as in mouse serum. Its use should facilitate the analysis of culture system or mouse model in which the hormonal activity of Osteocalcin needs to be evaluated.
Caren M. Gundberg - One of the best experts on this subject based on the ideXlab platform.
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Influence of carboxylation on Osteocalcin detection by mass spectrometry.
Rapid communications in mass spectrometry : RCM, 2016Co-Authors: Timothy P. Cleland, Caren M. Gundberg, Corinne J. Thomas, Deepak VashishthAbstract:Rationale Osteocalcin is a small, abundant bone protein that is difficult to detect using high-throughput tandem mass spectrometry (MS/MS) proteomic approaches from bone protein extracts, and is predominantly detected by non-MS immunological methods. Here, we analyze bovine Osteocalcin and its post-translational modifications to determine why a protein of this size goes undetected. Methods Osteocalcin was purified from cow bone using well-established methods. Intact Osteocalcin or trypsin-digested Osteocalcin were separated using an Agilent 1200 series high-performance liquid chromatography (HPLC) system and analyzed using a ThermoScientific LTQ-Orbitrap XL after fragmentation with higher-energy collision dissociation. Data were analyzed using Mascot or Prosight Lite. Results Our results support previous findings that the cow Osteocalcin has up to three carboxylations using both intact Osteocalcin and digested forms. Using Mascot, we were able to detect Osteocalcin peptides, but no fragments that localized the carboxylations. Full annotation using Prosight Lite of the intact (three carboxylations), N-terminal peptide (one carboxylation), and middle peptide (two carboxylations) showed complete fragmentation was present, but complete neutral loss was observed. Conclusions Osteocalcin carboxylation, and its associated neutral losses, makes high-throughput detection of this protein challenging; however, alternative fragmentation or limited purification can overcome these challenges. Copyright © 2016 John Wiley & Sons, Ltd.
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The role of Osteocalcin in human glucose metabolism: marker or mediator?
Nature reviews. Endocrinology, 2012Co-Authors: Sarah L Booth, Amanda Centi, Steven R. Smith, Caren M. GundbergAbstract:Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Here, the evidence for a role of Osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin-K-dependent, γ-carboxylated form. The concentration of Osteocalcin in the circulation is a measure of bone formation. The undercarboxylated form of Osteocalcin is active in glucose metabolism in mice. Total serum Osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism; however, human data are inconclusive with regard to the role of uncarboxylated Osteocalcin in glucose metabolism because most studies do not account for the influence of vitamin K on the proportion of undercarboxylated Osteocalcin or differentiate between the total and uncarboxylated forms of Osteocalcin. Furthermore, most human studies do not concomitantly measure other bone turnover markers to isolate the role of Osteocalcin as a measure of bone formation from its effect on glucose metabolism. Carefully designed studies are required to define the role of Osteocalcin and its carboxylated or undercarboxylated forms in the regulation of glucose metabolism in humans.
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γ carboxylation of Osteocalcin and insulin resistance in older men and women
The American Journal of Clinical Nutrition, 2009Co-Authors: Kyla M Shea, Caren M. Gundberg, James B Meigs, Gerard E Dallal, Edward Saltzman, Makiko Yoshida, Paul F Jacques, Sarah L BoothAbstract:Background: The skeletal protein Osteocalcin is c-carboxylated by vitamin K. High serum uncarboxylated Osteocalcin reflects low vitamin K status. In vitro and animal studies indicate that high uncarboxylated Osteocalcin is associated with reduced insulin resistance. However, associations between Osteocalcin and measures of insulin resistance in humans are less clear. Objective: Our aim was to examine cross-sectional and longitudinal associations between circulating forms of Osteocalcin (total, uncarboxylated, and carboxylated) and insulin resistance in older men and women. Design: Cross-sectional associations between serum measures of total Osteocalcin, carboxylated Osteocalcin, and uncarboxylated Osteocalcin and insulin resistance were examined in 348 nondiabetic men and women (mean age: 68 y; 58% female) by using the homeostasis model assessment of insulin resistance (HOMA-IR). Associations between each form of Osteocalcin at baseline and 3-y change in HOMA-IR were examined in 162 adults (mean age: 69 y; 63% female) who did not receive vitamin K supplementation. Results: Lower circulating uncarboxylated Osteocalcin was not associated with higher HOMA-IR at baseline or at 3-y follow-up. Those in the lowest tertiles of total Osteocalcin and carboxylated Osteocalcin at baseline had higher baseline HOMA-IR (P = 0.006 and P = 0.02, respectively). The concentration of carboxylated Osteocalcin at baseline was inversely associated with a 3-y change in HOMA-IR (P = 0.002). Conclusions: In older adults, circulating uncarboxylated Osteocalcin was not associated with insulin resistance. In contrast, elevated carboxylated Osteocalcin and total Osteocalcin were associated with lower insulin resistance, which supports a potential link between skeletal physiology and insulin resistance in humans. The role of vitamin K status in this association remains unclear and merits further investigation. This trial is registered at clinicaltrials.gov as NCT00183001. Am J Clin Nutr 2009;90:1230‐5.
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vitamin k status and bone health an analysis of methods for determination of undercarboxylated Osteocalcin
The Journal of Clinical Endocrinology and Metabolism, 1998Co-Authors: Caren M. Gundberg, Sherril Nieman, Steven A Abrams, Harold N RosenAbstract:Recent studies suggest that fracture risk is associated with increased undercarboxylated Osteocalcin. Methods use differences in binding of undercarboxylated and fully carboxylated Osteocalcin to hydroxyapatite or barium sulfate. We evaluated these methods and found that results varied with the amount and preparation of the salts. Furthermore, patient samples with differing amounts of total Osteocalcin could not be directly compared. Errors in the determination of undercarboxylated Osteocalcin were minimized by expressing data as the percent of the total Osteocalcin in the sample, and correcting for the basal level of Osteocalcin using a polynomial equation derived from multiple binding curves. Errors from 5-15% in estimation of undercarboxylated Osteocalcin were observed without both of these corrections. When differing types of assays were employed (RIA, intact, N-terminal), results also were affected. In normal adults and children and in patients on long-term warfarin therapy, the percent Osteocalcin not bound to hydroxyapatite was lower when measured with an intact assay than by a polyclonal RIA. Differences were related to the amount of N-terminal Osteocalcin fragments, which had low affinity for hydroxyapatite and resulted in variable overestimation of undercarboxylated Osteocalcin. In a kit specific for uncarboxylated Osteocalcin, we found good discrimination between carboxylated and uncarboxylated intact Osteocalcin. However, the assay detected large Osteocalcin fragments and overestimated their concentration by up to 350%. Values for uncarboxylated Osteocalcin were not different in patients on coumadin compared with normal adults with this kit, but when normalized to the total intact Osteocalcin, percent uncarboxylated Osteocalcin was greater in patients on coumadin than in controls, as would be expected. Kit values for uncarboxylated Osteocalcin in normal children were higher than intact values in the same subject, because of the increased reactivity of the kit toward circulating fragments that were elevated in children. Thus, for estimation of undercarboxylated Osteocalcin, care must be taken to standardize the hydroxyapatite or barium sulfite used for binding, to correct for the basal level of Osteocalcin in the sample, to use immunoassays that do not detect small fragments, and to express the results as the percent of the total Osteocalcin in the sample. Without these precautions, the assessment of undercarboxylated Osteocalcin is not reliable.
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Analysis of Osteocalcin Expression in Transgenic Mice Reveals a Species Difference in Vitamin D Regulation of Mouse and Human Osteocalcin Genes
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 1997Co-Authors: Thomas L. Clemens, Hui Tang, Shigeto Maeda, Robert A. Kesterson, Francesco J. Demayo, J. Wesley Pike, Caren M. GundbergAbstract:A line of transgenic mice expressing a human Osteocalcin genomic fragment (hOClocus) and a murine MC3T3-E1 cell line containing a stably integrated human Osteocalcin promoter construct have been developed to characterize the osteogenic and hormonal regulation of human Osteocalcin in vivo and in vitro. In this study, we used these models to demonstrate a species difference in the regulation of the mouse and human Osteocalcin genes by vitamin D. Repeated administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to mice carrying the hOClocus transgene resulted in striking increases in serum human Osteocalcin, whereas serum mouse Osteocalcin levels were unchanged after 24 h and only modestly increased 48 h after the second dose of hormone. 1,25(OH)2D3 increased human calvarial mRNA expression by 1.8-fold and slightly decreased mouse Osteocalcin mRNA levels by approximately 1.2-fold. Furthermore, treatment of primary calvarial osteoblasts from these mice with 1,25(OH)2D3 increased human Osteocalcin production but inhibited mouse Osteocalcin protein accumulation. To investigate further the mechanism for the apparent species difference in vitamin D3 induction of mouse and human Osteocalcin, we examined the effect of 1,25(OH)2D3 in an MC3T3-E1 cell line (MC4) containing a stably integrated 3900 bp Osteocalcin promoter-luciferase construct. Treatment of MC4 cells with ascorbic acid resulted in parallel increases of the endogenous mouse Osteocalcin protein and luciferase reporter activity over a 12-day period. Continuous exposure of MC4 cells to 1,25(OH)2D3 resulted in time-and dose-dependent increases in the activity of the phOC3900 luciferase construct. By contrast, the hormone had no effect on mouse Osteocalcin protein concentrations and inhibited its induction by ascorbic acid. However, when cells were treated acutely with 1,25(OH)2D3 at later times during growth in ascorbic acid, the induction of mouse Osteocalcin protein was only partially inhibited. In conclusion, our results indicate that common osteogenic signals regulate both mouse and human Osteocalcin gene expression, but the mouse gene is resistant to induction by vitamin D. This species difference in vitamin D regulation of Osteocalcin appears to result from the failure of 1,25(OH)2D3 to transcriptionally activate the mouse Osteocalcin gene.
Weiping Jia - One of the best experts on this subject based on the ideXlab platform.
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inverse relationship between serum Osteocalcin levels and visceral fat area in chinese men
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Yuqian Bao, Rong Yang, Feifei Wang, Yaping Hao, Jianxin Dou, Weiping JiaAbstract:Objective: The relationship between serum Osteocalcin levels and body fat distribution remains unclear. This study aimed to investigate the association between serum Osteocalcin levels and visceral fat area (VFA) in Chinese men. Design: Total serum Osteocalcin levels were measured in 1768 Chinese men (22–75 yr old) by electrochemiluminescence immunoassay. VFA was quantified via magnetic resonance imaging. Correlation analyses were carried out for serum Osteocalcin levels and clinical parameters. Subgroup analysis was carried out to confirm the correlations using subjects with normal glucose tolerance and normal body mass index chosen from the entire study population. Results: Increased serum Osteocalcin levels were accompanied by a decreasing trend in all anthropometric indices of obesity, systolic blood pressure, blood glucose, insulin resistance index, triglycerides, free fatty acid, and C-reactive protein levels (all P < 0.05). The 50–75th (Osteocalcin level: 16.18–19.88 ng/ml) and 75th (≥19.89 ng/ml) ...
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serum levels of Osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in chinese men
Clinical Endocrinology, 2011Co-Authors: Yuqian Bao, Mi Zhou, Ye Wang, Leiqing Sun, Meifang Gao, Meng Wei, Weiping JiaAbstract:Objective Osteocalcin is a bone-derived protein and has been shown to play an important role in regulating glucose and fat metabolism. We therefore investigated the association of serum levels of Osteocalcin with the metabolic syndrome (MS) and coronary atherosclerosis in Chinese men. Research design and methods Serum Osteocalcin levels were measured by an electrochemiluminescence immunoassay in 181 men who underwent coronary angiography, and their association with the MS and the severity of coronary artery disease (CAD) were studied. Results Osteocalcin levels in patients with the MS were significantly lower compared with those in non-MS subjects (P < 0·001) and decreased correspondingly with the increasing number of components of the MS (P < 0·001). Multiple logistic regression analysis demonstrated that Osteocalcin was independently associated with the MS (OR = 0·060, 95%CI: 0·005–0·651). In multiple stepwise regression analysis, waist circumference (P = 0·001) and fasting plasma glucose (P = 0·002) were independently associated with serum Osteocalcin. Subgroup analysis in 60 subjects with normal glucose tolerance showed that serum Osteocalcin decreased significantly in patients with CAD compared with those without CAD (P = 0·029) and decreased significantly as the number of stenotic vessels increased (P = 0·033). Furthermore, serum Osteocalcin showed an independent correlation with coronary atherosclerosis index (standardized β = −0·497, P = 0·003). Conclusion Serum Osteocalcin is inversely associated with the MS as well as the severity of coronary atherosclerosis in Chinese men, supporting the new concept that bone has the reciprocal regulation with energy metabolism.
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serum Osteocalcin concentrations in relation to glucose and lipid metabolism in chinese individuals
European Journal of Endocrinology, 2009Co-Authors: Mi Zhou, Xiaoping Pan, Junling Tang, Yun Chao Gao, Xuhong Hou, Yuqian Bao, Weiping JiaAbstract:Objectives: Osteocalcin, a bone-derived protein, has recently been reported to affect energy metabolism. We investigated the relationship between serum Osteocalcin and parameters of adiposity, glucose tolerance, and lipid profile in Chinese subjects. Methods: Serum Osteocalcin was measured by electrochemiluminescence immunoassay in 254 men (128 with newly diagnosed type 2 diabetes mellitus (T2DM) and 126 with normal glucose tolerance (NGT)), 66 premenopausal women (33 with T2DM and 33 with NGT) as well as 180 postmenopausal women (92 with T2DM and 88 with NGT). Their associations with parameters of adiposity, glucose tolerance, and lipid profile were examined. Results: Serum Osteocalcin concentrations in diabetic patients were significantly lower than those in NGT subjects after adjusted for age, gender, and body mass index (PZ0.003). Postmenopausal women had higher Osteocalcin concentrations than premenopausal women and men (both P!0.001). Multiple stepwise regression analysis showed that age, %fat, high-density lipoprotein cholesterol, fasting plasma glucose, and fasting serum insulin were independently associated with Osteocalcin in men (P!0.05). Age and HbA1c were independently correlated with Osteocalcin in postmenopausal women. Besides age and HbA1c, serum triglyceride was also an independent factor influencing Osteocalcin in premenopausal women. In addition, Osteocalcin was also positively associated with homeostasis model assessment of b-cell function. Furthermore, multiple logistic regression analysis demonstrated that Osteocalcin was independently associated with T2DM. Conclusions: Serum Osteocalcin was closely associated with not only fat and glucose metabolism but also with lipid metabolism.
Mathieu Ferron - One of the best experts on this subject based on the ideXlab platform.
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In vivo analysis of the contribution of bone resorption to the control of glucose metabolism in mice
Molecular metabolism, 2013Co-Authors: Julie Lacombe, Gerard Karsenty, Mathieu FerronAbstract:Osteocalcin is a hormone produced in bones by osteoblasts and regulating energy metabolism. While Osteocalcin exists in two forms, γ-carboxylated and undercarboxylated only the latter appears to function as a hormone in vivo. It has been proposed recently that osteoclasts, the bone-resorbing cells, are responsible of decarboxylating, i.e. activating Osteocalcin. To address the role of osteoclasts in the maintenance of energy metabolism we analyzed mutant mouse strains harboring either an increase or a decrease in osteoclasts number. Osteoprotegerin-deficient mice that are characterized by an increase in the number of osteoclasts demonstrate an increase in serum levels of undercarboxylated Osteocalcin and are significantly more glucose tolerant than WT animals. Conversely, osteoclasts ablation in mice results in a decrease in serum undercarboxylated Osteocalcin levels and in reduced glucose tolerance. These results support the notion that osteoclasts are controlling glucose metabolism at least in part through the regulation of Osteocalcin decarboxylation.
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Osteocalcin regulates murine and human fertility through a pancreas bone testis axis
Journal of Clinical Investigation, 2013Co-Authors: Franck Oury, Mathieu Ferron, Alexandre Chamouni, Prashanth Srinivas, Wang Huizhen, Cyrille Confavreux, Julie Lacombe, Francesca Lugani, Herve Lejeune, Rajendra T KumarAbstract:The osteoblast-derived hormone Osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates Osteocalcin's reproductive effects. Additionally, there is growing evidence that Osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of Osteocalcin is unclear. Using mouse models, we found that Osteocalcin and LH act in 2 parallel pathways and that Osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of Osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that Osteocalcin modulates reproductive function in humans.
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intermittent injections of Osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice
Bone, 2012Co-Authors: Mathieu Ferron, Patricia Ducy, Marc D Mckee, Robert L Levine, Gerard KarsentyAbstract:The uncarboxylated form of the osteoblast-specific secreted molecule Osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of Osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated Osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of Osteocalcin. We found that daily injections of Osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both β-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of Osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent Osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving Osteocalcin daily. Overall, these results provide evidence that daily injections of Osteocalcin can improve glucose handling and prevent the development of type 2 diabetes.
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An ELISA-based method to quantify Osteocalcin carboxylation in mice.
Biochemical and biophysical research communications, 2010Co-Authors: Mathieu Ferron, Jianwen Wei, Tatsuya Yoshizawa, Patricia Ducy, Gerard KarsentyAbstract:Osteocalcin was recently identified as an osteoblast-secreted hormone regulating insulin secretion and sensitivity. In mice and humans, Osteocalcin can be present in the serum in carboxylated or undercarboxylated forms and it has been shown that it is the undercarboxylated form of Osteocalcin which acts as a hormone. The study of Osteocalcin different circulating forms in mouse serum, however, has been hampered by the absence of quantitative methodology. Here we described a triple enzyme-linked immunosorbent assay (ELISA) system for quantification of mouse total, carboxylated and uncarboxylated Osteocalcin. That carboxylation of Osteocalcin was decreased in mouse osteoblasts cultures treated with warfarin, an inhibitor of carboxylation validated this assay. This ELISA could also detect elevated levels of undercarboxylated Osteocalcin in the serum of mice treated with warfarin and in the serum of Esp -/- mice, a mouse model known to have more undercarboxylated, i.e., active Osteocalcin. These results show that this new ELISA system is a reliable method to assess carboxylation status of Osteocalcin in cell culture supernatants as well as in mouse serum. Its use should facilitate the analysis of culture system or mouse model in which the hormonal activity of Osteocalcin needs to be evaluated.
Sarah L Booth - One of the best experts on this subject based on the ideXlab platform.
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relationship between chronic kidney disease glucose homeostasis and plasma Osteocalcin carboxylation and fragmentation
Journal of Renal Nutrition, 2020Co-Authors: Sarah L Booth, Mario Kratz, Leila R Zelnick, Olgica Trenchevska, Joshua W Jeffs, Chad R Borges, Hsin Hui Tseng, Bryan KestenbaumAbstract:Objective Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein Osteocalcin may promote insulin resistance. We assessed relationships of Osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study. Methods We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate Results The total plasma Osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more Osteocalcin was circulating as fragments. The extent of Osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses. Conclusions In CKD, circulating Osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, Osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in Osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
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The role of Osteocalcin in human glucose metabolism: marker or mediator?
Nature reviews. Endocrinology, 2012Co-Authors: Sarah L Booth, Amanda Centi, Steven R. Smith, Caren M. GundbergAbstract:Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Here, the evidence for a role of Osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin-K-dependent, γ-carboxylated form. The concentration of Osteocalcin in the circulation is a measure of bone formation. The undercarboxylated form of Osteocalcin is active in glucose metabolism in mice. Total serum Osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism; however, human data are inconclusive with regard to the role of uncarboxylated Osteocalcin in glucose metabolism because most studies do not account for the influence of vitamin K on the proportion of undercarboxylated Osteocalcin or differentiate between the total and uncarboxylated forms of Osteocalcin. Furthermore, most human studies do not concomitantly measure other bone turnover markers to isolate the role of Osteocalcin as a measure of bone formation from its effect on glucose metabolism. Carefully designed studies are required to define the role of Osteocalcin and its carboxylated or undercarboxylated forms in the regulation of glucose metabolism in humans.
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γ carboxylation of Osteocalcin and insulin resistance in older men and women
The American Journal of Clinical Nutrition, 2009Co-Authors: Kyla M Shea, Caren M. Gundberg, James B Meigs, Gerard E Dallal, Edward Saltzman, Makiko Yoshida, Paul F Jacques, Sarah L BoothAbstract:Background: The skeletal protein Osteocalcin is c-carboxylated by vitamin K. High serum uncarboxylated Osteocalcin reflects low vitamin K status. In vitro and animal studies indicate that high uncarboxylated Osteocalcin is associated with reduced insulin resistance. However, associations between Osteocalcin and measures of insulin resistance in humans are less clear. Objective: Our aim was to examine cross-sectional and longitudinal associations between circulating forms of Osteocalcin (total, uncarboxylated, and carboxylated) and insulin resistance in older men and women. Design: Cross-sectional associations between serum measures of total Osteocalcin, carboxylated Osteocalcin, and uncarboxylated Osteocalcin and insulin resistance were examined in 348 nondiabetic men and women (mean age: 68 y; 58% female) by using the homeostasis model assessment of insulin resistance (HOMA-IR). Associations between each form of Osteocalcin at baseline and 3-y change in HOMA-IR were examined in 162 adults (mean age: 69 y; 63% female) who did not receive vitamin K supplementation. Results: Lower circulating uncarboxylated Osteocalcin was not associated with higher HOMA-IR at baseline or at 3-y follow-up. Those in the lowest tertiles of total Osteocalcin and carboxylated Osteocalcin at baseline had higher baseline HOMA-IR (P = 0.006 and P = 0.02, respectively). The concentration of carboxylated Osteocalcin at baseline was inversely associated with a 3-y change in HOMA-IR (P = 0.002). Conclusions: In older adults, circulating uncarboxylated Osteocalcin was not associated with insulin resistance. In contrast, elevated carboxylated Osteocalcin and total Osteocalcin were associated with lower insulin resistance, which supports a potential link between skeletal physiology and insulin resistance in humans. The role of vitamin K status in this association remains unclear and merits further investigation. This trial is registered at clinicaltrials.gov as NCT00183001. Am J Clin Nutr 2009;90:1230‐5.
