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Endocrinology Aug 1997
Topics: Animals; Bone and Bones; Calcium; Humans; Mice; Osteocalcin; Parathyroid Hormone; Type C Phospholipases
PubMed: 9231753
DOI: 10.1210/endo.138.8.5383 -
Biochimica Et Biophysica Acta.... Apr 2024Recent findings suggest that uncarboxylated osteocalcin (GluOC) promotes glucose and lipid metabolism via its putative receptor GPRC6A; however, its direct effect on...
Recent findings suggest that uncarboxylated osteocalcin (GluOC) promotes glucose and lipid metabolism via its putative receptor GPRC6A; however, its direct effect on adipocytes remains elusive. In this study, we elucidated the effects of GluOC on adipocytes, with an emphasis on the role of cell adhesion molecules. We determined that GluOC promoted the expression of adipocyte adhesion molecule (ACAM) and its transcription factor Krüppel-like factor 4 and enhanced the cortical actin filament assembly, which ameliorated lipid droplet hypertrophy. Additionally, GluOC upregulated the expression of integrin αVβ3 and activation of focal adhesion kinase (FAK) and prevented insulin receptor substrate 1 (IRS1) degradation by inhibiting the ubiquitin-proteasome system via the FAK-PLC-PKC axis, which activated IRS1-Akt-mediated glucose transporter 4 (GLUT4) transport. Furthermore, we showed that GluOC elevated the expression of the insulin-independent glucose transporters GLUT1 and GLUT8, which facilitated insulin stimulation-independent glucose transport. The GluOC-induced activation of integrin αVβ3 signaling promoted microtubule assembly, which improved glucose and lipid metabolism via its involvement in intracellular vesicular transport. GluOC treatment also suppressed collagen type 1 formation, which might prevent adipose tissue fibrosis in obese individuals. Overall, our results imply that GluOC promotes glucose and lipid metabolism via ACAM, integrin αVβ3, and GLUT1 and 8 expression, directly affecting adipocytes.
Topics: Humans; Glucose; Osteocalcin; Lipid Metabolism; Glucose Transporter Type 1; Integrin alphaVbeta3; Adipocytes; Insulin; Cell Adhesion Molecules
PubMed: 38417588
DOI: 10.1016/j.bbamcr.2024.119701 -
Cellular and Molecular Neurobiology Nov 2012Immunohistochemistry for osteocalcin (OC) and osteopontin (OPN) was performed to know their distributions in the hind brain of adult rats. OC- and OPN-immunoreactivity...
Immunohistochemistry for osteocalcin (OC) and osteopontin (OPN) was performed to know their distributions in the hind brain of adult rats. OC- and OPN-immunoreactivity (-ir) were detected in neuronal cell bodies, including perikarya and proximal dendrites and the neuropil. In the cranial nerve motor nuclei, numerous OC- and OPN-immunoreactive (-ir) neurons were detected. The neuropil in the cranial motor nuclei mostly showed strong OC- and OPN-staining intensity. The cranial nerve sensory nuclei and other relay and modulating structures in the lower brain stem also contained various numbers of OC- and OPN-ir neurons. The staining intensities in the neuropil were varied among these regions. In the cerebellar cortex, Purkinje cells and granule cells showed OPN-ir but not OC-ir. However, OC- and OPN-ir neurons were abundantly distributed throughout the cerebellar nuclei. The neuropil in the cerebellar nuclei showed moderate OC-ir and strong OPN-ir staining intensities. These findings indicate that the distribution patterns of OC- and OPN-ir neurons were similar in many structures within the hind brain. OC may play a role in modulating neuroprotective function of OPN.
Topics: Animals; Male; Neurons; Osteocalcin; Osteopontin; Rats; Rats, Sprague-Dawley; Rhombencephalon
PubMed: 22552891
DOI: 10.1007/s10571-012-9851-1 -
ELife Jan 2021Osteocalcin is a bone matrix protein that acts like a hormone when it reaches the blood, and has different effects in mice and humans.
Osteocalcin is a bone matrix protein that acts like a hormone when it reaches the blood, and has different effects in mice and humans.
Topics: Animals; Glycosylation; Hormones; Mice; Osteocalcin
PubMed: 33480844
DOI: 10.7554/eLife.65719 -
Journal of Agricultural and Food... Apr 2023Osteocalcin was reported to regulate muscle energy metabolism, thus fighting fatigue during exercise. The current work aimed to investigate the anti-fatigue effect and...
Osteocalcin was reported to regulate muscle energy metabolism, thus fighting fatigue during exercise. The current work aimed to investigate the anti-fatigue effect and the underlying mechanism of a homogeneous polysaccharide (PCPY-1) from after structure characterization. In the exhaustive swimming mouse model and the co-culture system of BMSCs/C2C12 cells, PCPY-1 significantly stimulated BMSC differentiation into osteoblasts as determined by ALP activity, matrix mineralization, and the protein expressions of osteogenic markers BMP-2, phosphor-Smad1, RUNX2, and osteocalcin. Meanwhile, PCPY-1 remarkably enhanced myoblast energy metabolism by upregulating osteocalcin release and GPRC6A protein expression; the phosphorylation levels of CREB and HSL; the mRNA levels of GLUT4, CD36, FATP1, and CPT1B; and ATP production in vitro and in vivo. Accordingly, PCPY-1 exhibited good anti-fatigue capacity in mice as confirmed by fatigue-related indicators. Our findings indicated PCPY-1 could enhance osteocalcin-mediated communication between bones and muscles, which was conducive to muscle energy metabolism and ATP generation, thus alleviating fatigue in exhausted swimming mice.
Topics: Mice; Animals; Osteocalcin; Polygonatum; Cell Differentiation; Osteoblasts; Muscles; Polysaccharides; Adenosine Triphosphate; Receptors, G-Protein-Coupled
PubMed: 37043685
DOI: 10.1021/acs.jafc.2c08192 -
Frontiers in Endocrinology 2020
Topics: Animals; Bone and Bones; Endocrine System; Energy Metabolism; Homeostasis; Humans; Osteocalcin; Osteoclasts
PubMed: 33178138
DOI: 10.3389/fendo.2020.591085 -
Medicine Oct 2023To systematically evaluate the correlation between serum osteocalcin levels and cognitive function status in type 2 diabetes mellitus (T2D) patients. (Meta-Analysis)
Meta-Analysis
BACKGROUND
To systematically evaluate the correlation between serum osteocalcin levels and cognitive function status in type 2 diabetes mellitus (T2D) patients.
METHODS
This review was conducted according to the PRISMA guidelines, and was developed and submitted to PROSPERO (CRD42022339295). We comprehensively searched PubMed, EMBASE, Web of Science, Scopus, ProQuest, and Chinese Databases (China National Knowledge Infrastructure, Wan Fang, Chinese Science and Technology Periodical Database, and China Biology Medicine) up to 1 June 2023. 3 investigators performed independent literature screening and data extraction of the included literature, and 2 investigators performed an independent quality assessment of case-control studies using the Newcastle-Ottawa-Scale tool. Data analysis was performed using Review Manager 5.4 software. For continuous various outcomes, mean difference (MD) or standardized MD with 95% confidence intervals (CIs) was applied for assessment by fixed-effect or random-effect model analysis. The heterogeneity test was performed by the Q statistic and quantified using I2, and publication bias was evaluated using a funnel plot.
RESULTS
9 studies with T2D were included (a total of 1310 subjects). Meta-analysis results indicated that cognitive function was more impaired in patients with lower serum osteocalcin levels [MD = 9.91, 95% CI (8.93, -10.89), I2 = 0%]. Serum osteocalcin levels were also significantly different between the 2 groups of T2D patients based on the degree of cognitive impairment [MD = -0.93, 95% CI (-1.09, -0.78), I2 = 41%]. It summarized the statistical correlation between serum osteocalcin and cognitive function scores in patients with T2D at r = 0.43 [summary Fisher's Z = 0.46, 95% CI (0.39, -0.50), I2 = 41%). After sensitivity analysis, the heterogeneity I2 decreased to 0%, indicating that the results of the meta-analysis are more reliable.
CONCLUSION SUBSECTIONS
Based on a meta-analysis of included studies, we concluded that there is a moderately strong positive correlation between serum osteocalcin levels and patients' cognitive function in T2D. An intervention to increase serum osteocalcin levels can contribute to delaying and improving cognitive decline in patients with T2D.
Topics: Humans; Case-Control Studies; Cognition; Diabetes Mellitus, Type 2; Functional Status; Osteocalcin
PubMed: 37832077
DOI: 10.1097/MD.0000000000034440 -
Endocrinology Nov 2016The undercarboxylated form of osteocalcin (ucOC) regulates male fertility and energy metabolism, acting through the G protein-coupled receptor (GPRC)6A, thus forming a...
The undercarboxylated form of osteocalcin (ucOC) regulates male fertility and energy metabolism, acting through the G protein-coupled receptor (GPRC)6A, thus forming a new pancreas-bone-testis axis. Recently, GPRC6A has also been suggested to mediate the nongenomic responses of free testosterone (T). However, these data did not consider the physiological scenario, where circulating T is mainly bound to sex hormone-binding globulin (SHBG) and only a small percentage circulates freely in the blood. Here, by the use of computational modelling, we document the existence of similar structural moieties between ucOC and SHBG that are predicted to bind to GPRC6A at docking analysis. This hypothesis of competition was assessed by binding experiments on human embryonic kidney-293 cells transfected with human GPRC6A gene. Unliganded SHBG specifically bound the membrane of human embryonic kidney-293 cells transfected with GPRC6A and was displaced by ucOC when coincubated at 100-fold molar excess. Furthermore, specific downstream Erk1/2 phosphorylation after stimulation of GPRC6A with ucOC was significantly blunted by 100-fold molar excess of unliganded SHBG. Intriguingly previous incubation with unliganded SHBG, followed by incubation with T, induced Erk1/2 phosphorylation in a dose-dependent manner. Neither binding nor stimulating activities were shown for SHBG saturated with T. Experiments on mutation constructs of GPRC6A strengthened the hypothesis of a common binding site of ucOC and SHBG. Given the role of GPRC6A on energy metabolism, these data agree with epidemiological association between SHBG levels and insulin sensitivity, suggest GPRC6A as a likely SHBG receptor, and add bases for the possible regulation of androgen activity in a nonsteroidal manner.
Topics: Binding Sites; Energy Metabolism; Fluorescent Antibody Technique; HEK293 Cells; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Osteocalcin; Phosphorylation; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Sex Hormone-Binding Globulin
PubMed: 27673554
DOI: 10.1210/en.2016-1312 -
Frontiers in Bioscience (Landmark... Jun 2014Osteocalcin (OCN) is a small noncollagenous protein mainly produced by osteoblasts and is highly represented in bones of most vertebrates. Human OCN contains up to three...
Osteocalcin (OCN) is a small noncollagenous protein mainly produced by osteoblasts and is highly represented in bones of most vertebrates. Human OCN contains up to three gamma-carboxyglutamic acid (Gla-OCN) residues at positions 17, 21 and 24 which are thought to increase calcium binding strength, improving mechanical properties of the bone matrix. Recent studies revealed that OCN exerts also important endocrine functions, affecting energy metabolism and male fertility. The latter effect seems to be mediated by the uncarboxylated form of OCN (Glu-OCN). We employed human and mouse OCN as models of fully carboxylated and uncarboxylated OCN forms to investigate, by the use of circular dichroism and molecular dynamics simulations, the respective conformational properties and Ca2+ affinity. Ca2+ binding was found to trigger a similar conformational transition in both Glu-OCN and Gla-OCN, from a disordered structure to a more compact/stable form. Notably, gamma-carboxylation increases the affinity of OCN for Ca2+ by > 30 fold suggesting that, in physiological conditions, Gla-OCN is essentially Ca2+-bound, whereas Glu-OCN circulates mainly in the Ca2+-free form.
Topics: 1-Carboxyglutamic Acid; Amino Acid Sequence; Animals; Binding, Competitive; Calcium; Carboxylic Acids; Circular Dichroism; Glutamic Acid; Humans; Kinetics; Mice; Molecular Dynamics Simulation; Molecular Sequence Data; Osteocalcin; Protein Binding; Protein Conformation; Protein Stability; Sequence Homology, Amino Acid; Thermodynamics
PubMed: 24896339
DOI: 10.2741/4270 -
Journal of Bone and Mineral Research :... Jul 1997Plasmin cleaves osteocalcin at a site within its carboxyl end, thus creating an N-midterminal 1-43 and a short C-terminal 44-49 peptides. The products of the cleavage...
Plasmin cleaves osteocalcin at a site within its carboxyl end, thus creating an N-midterminal 1-43 and a short C-terminal 44-49 peptides. The products of the cleavage were identified by matrix assisted laser desorption ionization time of flight mass spectrophotometry and by reversed phase high performance liquid chromatography followed by N-terminal sequence determination. When separated by sodium dodecyl sulfide-polyacrylamide gel electrophoresis in the presence of reducing agents, large (LF; N-midterminal) and a small molecular weight (SF; C-terminal) fragments can be identified. The major cleavage site involves arg43-arg44 amino acid residues, and the resulting 44-49 C-terminal fragment appears as a slow migrating band on native gels (SFnat). Elevated levels of calcium ion inhibit the plasmin-mediated lysis of osteocalcin. Plasmin-mediated cleavage of osteocalcin occurs both in solution and when bound to hydroxyapatite. Both osteocalcin cleavage products detach from the hydroxyapatite substrate. Diisopropyl fluorophosphate-inhibited plasmin does not displace osteocalcin from the hydroxyapatite surface. Previously, the C-terminal pentapeptide has been shown to be chemotactic for bone cells while bone particles lacking osteocalcin were resistant to bone resorption. We therefore hypothesize that the plasmin-mediated digestion of free and hydroxyapatite-bound osteocalcin could play a role in the regulation of bone remodeling.
Topics: Amino Acid Sequence; Binding Sites; Bone Remodeling; Chromatography, High Pressure Liquid; Fibrinolysin; Humans; Hydroxyapatites; In Vitro Techniques; Molecular Weight; Osteocalcin; Peptide Fragments; Solutions; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PubMed: 9200002
DOI: 10.1359/jbmr.1997.12.7.1035