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Acta Pharmacologica Sinica Mar 2020Osteocalcin, expressed in osteoblasts of the bone marrow, undergoes post-translational carboxylation and deposits in mineralized bone matrix. A portion of osteocalcin...
Osteocalcin, expressed in osteoblasts of the bone marrow, undergoes post-translational carboxylation and deposits in mineralized bone matrix. A portion of osteocalcin remains uncarboxylated (uncarboxylated osteocalcin, GluOC) that is released into blood where it functions as a hormone to regulate insulin secretion and insulin sensitivity. As insulin resistance is closely associated with metabolic syndrome, this study is aimed to elucidate how GluOC regulates glucose and lipid metabolism in KKAy mice, an animal model displaying obese, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. GluOC (3, 30 ng/g per day, ig) was orally administered to female KKAy mice for 4 weeks. Whole-body insulin sensitivity, glucose metabolism, hepatic steatosis, dyslipidemia were examined using routine laboratory assays. We found that GluOC administration significantly enhanced insulin sensitivity in KKAy mice by activating hepatic IRβ/PI3K/Akt pathway and elevated the whole-body insulin sensitivity with decreased FPI and HOMA-IR index. Furthermore, GluOC administration alleviated hyperglycemia through suppressing gluconeogenesis and promoting glycogen synthesis in KKAy mice and in cultured hepatocytes in vitro. Moreover, GluOC administration dose-dependently ameliorated dyslipidemia and attenuated hepatic steatosis in KKAy mice by inhibiting hepatic de novo lipogenesis and promoting fatty-acid β-oxidation. These results demonstrate that GluOC effectively enhances hepatic insulin sensitivity, improves hyperglycemia and ameliorates hepatic steatosis in KKAy mice, suggesting that GluOC could be a promising drug candidate for treating metabolic syndrome.
Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Glucose Tolerance Test; Insulin; Lipid Metabolism; Liver; Mice; Mice, Obese; Osteocalcin; Signal Transduction
PubMed: 31659239
DOI: 10.1038/s41401-019-0311-z -
Gaceta Medica de Mexico 2018Osteocalcin has been shown to have an inverse relationship with blood glucose, insulin resistance and adiposity.
INTRODUCTION
Osteocalcin has been shown to have an inverse relationship with blood glucose, insulin resistance and adiposity.
OBJECTIVE
To determine osteocalcin normal serum concentration in Mexican healthy adults and compare it with values reported in other populations.
METHOD
Carboxylated and undercarboxylated osteocalcin serum concentrations were determined in 100 healthy adults by means of enzyme immunoassay; osteocalcin total concentration was calculated. A descriptive comparison was made with other populations' values reported in the literature.
RESULTS
Carboxylated and undercarboxylated osteocalcin median concentrations were 3.22 ng/mL and 1.61 ng/mL, respectively. Mean total osteocalcin was 7.40 ± 5.11 ng/mL. There was no significant difference between the osteocalcin values in our population and those of populations where similar quantification methods to ours were used.
CONCLUSION
Osteocalcin total serum concentration mean in the analyzed population was 7.40 ng/mL. There are subtle variations between populations that are attributable to genetic and population factors; however, the quantification method was the only variable that was shown to significantly influence on osteocalcin levels in healthy populations.
Topics: Female; Global Health; Humans; Male; Middle Aged; Osteocalcin; Reference Values
PubMed: 29733058
DOI: 10.24875/GMM.18002564 -
Biology of the Neonate 1993
Topics: Adult; Breast Feeding; Cell Count; Female; Humans; Lactation; Leukocyte Count; Milk, Human; Osteocalcin; Postpartum Period; Radioimmunoassay
PubMed: 8443295
DOI: 10.1159/000243909 -
Archives of Endocrinology and Metabolism Jun 2018
Topics: Bone and Bones; Energy Metabolism; Humans; Osteocalcin; Osteogenesis
PubMed: 29972433
DOI: 10.20945/2359-3997000000050 -
Cancer Investigation 1990
Topics: Biomarkers, Tumor; Bone Neoplasms; Osteocalcin
PubMed: 2207769
DOI: 10.3109/07357909009012062 -
Calcified Tissue International Nov 2011The tumor-suppressor p53 is a transcription factor that regulates a number of genes in the process of cell-cycle inhibition, apoptosis, and DNA damage. Recent studies...
The tumor-suppressor p53 is a transcription factor that regulates a number of genes in the process of cell-cycle inhibition, apoptosis, and DNA damage. Recent studies have revealed a crucial role for p53 in bone remodeling. In our previous studies we have shown that p53 is an important regulator of osteoblast differentiation. In this study we investigated the role of p53 in the regulation of human osteocalcin gene expression. We observed that osteocalcin promoter activity could be upregulated by both exogenous and endogenous p53 and downregulated by p53-specific small interfering RNA. DNA affinity immunoblotting assay showed that p53 can bind to the human osteocalcin promoter in vitro. We further identified a p53 response element within the osteocalcin promoter region using a chromatin immunoprecipitation assay. Furthermore, we observed an additive effect of p53 and VDR on the regulation of osteocalcin promoter activity. Our findings suggest that p53 may directly target the human osteocalcin gene and positively affect osteocalcin gene expression.
Topics: Animals; Base Sequence; Bone Remodeling; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation; Humans; Molecular Sequence Data; Osteocalcin; Promoter Regions, Genetic; Rats; Transfection; Tumor Suppressor Protein p53; Up-Regulation
PubMed: 21964930
DOI: 10.1007/s00223-011-9533-x -
Chembiochem : a European Journal of... Jul 2011
Topics: Amino Acid Sequence; Animals; Bone and Bones; Durapatite; Humans; Mice; Mice, Nude; Molecular Sequence Data; Osteocalcin; Peptidomimetics
PubMed: 21661088
DOI: 10.1002/cbic.201100162 -
Journal of Endocrinological... Aug 2020Under-carboxylated osteocalcin (UcOC), a bone-released hormone is suggested to regulate energy metabolism. Pregnancy and lactation physiological conditions that require...
PURPOSE
Under-carboxylated osteocalcin (UcOC), a bone-released hormone is suggested to regulate energy metabolism. Pregnancy and lactation physiological conditions that require high levels of energy. The current study attempts to examine whether UcOC is involved in regulating energy metabolism during these conditions using adult Wistar rats.
METHODS AND RESULTS
Insulin tolerance tests indicated insulin resistance during late pregnancy (day 19 of pregnancy; P19) and insulin sensitivity during early lactation (day 6 of lactation; L6). Gene expression analyses suggested that muscle glucose metabolism was downregulated during P19 and enhanced during L6. Concomitantly, circulatory UcOC levels were lower during pregnancy but higher during early lactation; the rise in UcOC levels was tightly linked to the lactation process. Altering endogenous UcOC levels pharmacologically with warfarin and alendronate in P19 and L6 rats changed whole-body insulin response and muscle glucose transporter (Glut4) expression. Glut4 expression can be increased by either UcOC or estrogen receptors (ERs), both of which act independent of each other. A high fat diet decreased UcOC levels and insulin sensitivity in lactating rats, suggesting that diet can compromise UcOC-established energy homeostasis. Gene expression of lipid metabolism markers and triglyceride levels suggested that UcOC suppression during early pregnancy is an essential step in maternal lipid storage.
CONCLUSION
Taken together, we found that UcOC plays an important role in energy homeostasis via regulation of glucose and lipid metabolism during pregnancy and lactation.
Topics: Animals; Carboxylic Acids; Energy Metabolism; Female; Glucose; Homeostasis; Lactation; Lipid Metabolism; Male; Osteocalcin; Pregnancy; Rats; Rats, Wistar
PubMed: 32056149
DOI: 10.1007/s40618-020-01195-8 -
Revue Du Rhumatisme (Ed. Francaise :... Jun 1994Smoking is a risk factor for osteoporosis. Nicotine and nonnicotine tobacco smoke components have been shown to depress osteoblast activity in a number of in vitro and...
Smoking is a risk factor for osteoporosis. Nicotine and nonnicotine tobacco smoke components have been shown to depress osteoblast activity in a number of in vitro and animal studies. To determine whether smoking is associated with depressed osteoblast activity in humans, we measured serum osteocalcin levels (using a radioimmunological method based on an antibody to human osteocalcin) in 24 male or female smokers and 24 matched nonsmokers. Overall, osteocalcin levels were significantly lower in smokers (15 +/- 6.95 ng/ml) than in nonsmokers (21.27 +/- 8.34 ng/ml) (p = 0.007). The difference between smokers and nonsmokers was significant in males (15.3 +/- 4.5 vs 23.27 +/- 9.7; p = 0.02) but not in females (16.27 +/- 8.9 vs 19.45 +/- 6.7; p = 0.2). These data suggest that smoking may induce osteoblast depression, either directly or via hormonal changes.
Topics: Adult; Bone Remodeling; Female; Humans; Male; Osteoblasts; Osteocalcin; Sex Factors; Smoking
PubMed: 7833868
DOI: No ID Found -
The Biochemical Journal Jul 1999Vitamin K-dependent proteins contain a propeptide that is required for recognition by the enzyme gamma-glutamylcarboxylase. Substrates used in vitro for carboxylation...
Vitamin K-dependent proteins contain a propeptide that is required for recognition by the enzyme gamma-glutamylcarboxylase. Substrates used in vitro for carboxylation studies lacking a prosequence are characterized by Km values in the millimolar range, whereas the Km for peptides containing a prosequence is three or four orders of magnitude smaller. Here we report that descarboxy-osteocalcin is an exception in this respect. With descarboxy-osteocalcin in purified propeptide-free recombinant carboxylase, the Km was 1.8 microM. Furthermore, osteocalcin was an inhibitor of descarboxy-osteocalcin carboxylation with a Ki of 76 microM. In contrast with the other vitamin K-dependent proteins, free propeptides do not inhibit descarboxy-osteocalcin carboxylation. Moreover, propeptide-containing substrates were inhibited neither by osteocalcin nor by its propeptide. From our studies we conclude that descarboxy-osteocalcin must have an internal recognition sequence that binds to gamma-glutamylcarboxylase at a site different from the propeptide-recognition site.
Topics: Amino Acid Sequence; Animals; Binding Sites; Carbon-Carbon Ligases; Cell Line; Molecular Sequence Data; Osteocalcin; Peptides; Protein Binding; Substrate Specificity; Vitamin K
PubMed: 10393081
DOI: No ID Found