osteoprotegerin and Obesity

To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases.. The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.

Topics: Diabetes Mellitus, Type 2; Humans; Ligands; NF-kappa B; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease (NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome (MetS), like insulin resistance (IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, MetS, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin (OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesity-related comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of MetS as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

Topics: Animals; Comorbidity; Humans; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; Prevalence; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.

Topics: Aging; Aortic Diseases; Atherosclerosis; Blood Flow Velocity; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Gene Expression; Humans; Inflammation; Lipids; Obesity; Osteoprotegerin; Polymorphism, Genetic; Prognosis; Vascular Calcification

Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily of cytokines which, in spite of being initially described as a strong anti-resorptive factor, has lately been considered as a possible link between bone and vascular disease. In the last few years, several studies have evidenced its close relationship with the development of diabetes. In this review, we analyse the role of OPG in diabetic patients and its links with the most relevant associated diseases such as atherosclerosis, hypertension, endothelial dysfunction and diabetic nephropathy, as well as its connection with related pathologies as fibrosis, obesity and metabolic syndrome.

Topics: Atherosclerosis; Diabetes Complications; Diabetic Nephropathies; Fibrosis; Humans; Hypertension; Metabolic Syndrome; Obesity; Osteoprotegerin

Several single-nucleotide polymorphisms (SNPs) have been reliably associated with areal bone mineral density (aBMD) in genome-wide association studies of mostly older subjects.. We aimed to test those SNPs for an association with peripheral quantitative computed tomography (pQCT) bone measures in two young cohorts.. We genotyped nine SNPs from the most promising aBMD candidates in a cohort of 15-yr-olds [in the Avon Longitudinal Study of Parents and Children (ALSPAC)] and carried out association analysis with several tibial pQCT measures to determine whether these candidates were important during adolescent growth and which particular skeletal parameters each of the candidates were acting upon. We also carried out a metaanalysis of the SNPs for association with cortical bone mineral density (BMDC) in ALSPAC and a similar male-only study (Gothenburg Osteoporosis and Obesity Determinants).. In the ALSPAC cohort, we found a significant association between RANK SNP (rs3018362) and BMDC but not any of the other pQCT bone measures. In the metaanalysis, we found the OPG SNP (rs4355801) and the RANK SNP (rs3018362) to be significantly associated with BMDC. We also found suggestive evidence of an association between the MARK3 SNP (rs2010281) and BMDC but with a direction of effect opposite to that previously reported.. The association of genes from the RANK/RANKL/OPG pathway and BMDC provides new insight into how this system might affect the skeleton, confirming it to be associated with volumetric cortical bone density but observing no relationship with bone size.

Topics: Adolescent; Adult; Bone Density; Child; Female; Genetic Association Studies; Genotype; Humans; Longitudinal Studies; Male; Obesity; Osteoporosis; Osteoprotegerin; Patient Selection; Polymorphism, Single Nucleotide; Receptor Activator of Nuclear Factor-kappa B

Recent studies indicate that obesity is not a risk factor of osteoporosis. On the contrary, increased adipose tissue mass may have a protective effect against osteoporosis. This suggests that the positive influence of adipose tissue on bone tissue may be a consequence of the boost in load on the bone tissue, leading to increased bone anabolism. It may also be connected with changes frequently occurring in postmenopausal women in the formation of some osteotropic factors, mainly hormones such as estrogens, androgens, calciotropic hormones, somatotrophin axis hormones, leptin, and melatonin. The antiresorption effects of the above hormones on the bone are to a considerable extent executed through the RANKL/RANK/OPG system (receptor activator of nuclear factor-kB ligand/receptor activator of nuclear factor-kB/osteoprotegerin), the principal signaling pathway through which osteoblasts regulate the rate of the activated osteoclast pool. This effect may be achieved through a direct effect on the expressions OPG and/or RANKL in osteoblasts and marrow stroma cells and/or indirectly through cytokines, mainly interleukins (IL)-1 and -6, tumor necrosis factor-alpha(TNF-alpha), macrophage colony-stimulating factor (M-CSF), and tumor necrosis factor-beta (TNF-beta).

Topics: Female; Humans; Interleukin-1; Lymphotoxin-alpha; Macrophage Colony-Stimulating Factor; Menopause; Obesity; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Risk Factors; Tumor Necrosis Factor-alpha

Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 ± 10 years studied 7 ± 2 years after bariatric surgery. The variables studied were bone mineral density, β-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, β-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (β = -0.235, P = 0.046), percentage of weight loss (β = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio (β = 0.259, P = 0.029) in stepwise multivariate analysis (R

Topics: Adult; Aged; Bariatric Surgery; Biomarkers; Bone Density; Bone Diseases, Metabolic; Female; Humans; Middle Aged; Obesity; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Pelvic Bones; Postoperative Complications; RANK Ligand; Spine

To assess if altered bone turnover following bariatric surgery is related to metabolic consequences of the surgical procedure or weight loss. We evaluated serum markers reflecting bone turnover and metabolic pathways at baseline and after 1-year in a controlled non-randomized clinical trial comparing Roux-en-Y gastric bypass surgery (n = 74) with lifestyle intervention (n = 63) on obesity-related comorbidities. The decrease in body mass index (BMI) was larger in the surgery (-14.0 kg/m(2)) compared to lifestyle (-3.7 kg/m(2)). Markedly increased bone turnover was observed following surgery compared to lifestyle intervention and was correlated with change in BMI. Stepwise multivariable regression analysis revealed that group (β = 0.31, p < 0.01), and changes in BMI (β = -0.28, p < 0.01), dickkopf-1 (β = 0.20, p < 0.001) and sclerostin (β = 0.11, p < 0.05) were predictors of change in the bone resorption marker N-terminal telopeptide. Our data support that mechanisms related to the procedure itself and changes in secreted Wnt antagonists may contribute to increased bone turnover following bariatric surgery.

Topics: Adult; Biomarkers; Body Mass Index; Bone Remodeling; Calcium; Female; Gastric Bypass; Humans; Intercellular Signaling Peptides and Proteins; Life Style; Male; Middle Aged; Obesity; Osteoprotegerin; Parathyroid Hormone; Treatment Outcome; Vitamin D; Weight Loss

Our aim was to determine whether 12 weeks' aerobic Nordic walking (NW) or resistance exercise training (RT) without diet-induced weight loss could decrease oxidative stress and atherogenic index of plasma (AIP), prevalence of metabolic syndrome (MetS) and MetS score in middle-aged men with impaired glucose regulation (IGR) (n=144. 54.5 ± 6.5 years). In addition, we compared effects of intervention between overweight and obese subgroups. Prevalence of MetS and AIP index decreased only in NW group and MetS score in both NW and RT groups but not in control group. The changes in AIP index correlated inversely with changes in plasma antioxidant capacity. The change in AIP index remained a significant independent predictor of the changes in MetS score after the model was adjusted for age, BMI and volume of exercise (MET h/week) in NW group. There were no changes in the other measured markers of oxidative stress and related cytokines (e.g. osteopontin and osteoprotegerin) in any of the groups. Nordic walking decreased prevalence of MetS and MetS score. Improved lipid profile remained a predictor of decreased MetS score only in NW group and it seems that Nordic walking has more beneficial effects on cardiovascular disease risks than RT training.

Topics: Adult; Aged; Antioxidants; Atherosclerosis; Body Mass Index; Diet; Exercise; Glucose; Humans; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity; Osteopontin; Osteoprotegerin; Overweight; Oxidative Stress; Resistance Training; Walking

High serum levels of osteoprotegerin (OPG) are found in patients with obesity, type 2 diabetes, sepsis, or septic shock and are associated with a high mortality rate in stroke. The primary known function of OPG is to bind to the receptor activator of NF-

Topics: Diabetes Mellitus, Type 2; Humans; Inflammation; Lipopolysaccharides; Macrophages; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4

Obesity and diabetes prevalence are increasing worldwide. We aimed to detect the possible association of osteoprotegerin (OPG) gene expression with visceral adiposity indices and cardiometabolic risk factors among obese women.. The study enrolled 150 controls and 150 obese cases subdivided into two subgroups non-diabetic (n = 70) and 80 patients with type 2 diabetes mellitus (T2DM). Circulating OPG gene expression levels were figured out by real time PCR (Polymerase Chain Reaction). Serum OPG levels were assessed by Enzyme Linked Immunosorbent Assay. Our results explored that OPG serum levels were lower in the obese women compared to control group (p < 0.001) and obese diabetics had higher serum levels of OPG in comparison to obese non-diabetic patients (p < 0.001). Expression levels of OPG were higher in obese women than controls (p < 0.001). Moreover, the blood expression levels of OPG gene were higher in diabetic obese patients than non-diabetics. We found positive correlations between parameters of metabolic syndrome and obesity indices. After adjustment of the traditional risk factors, stepwise linear regression analysis test revealed that OPG expression levels were independently correlated with glycated hemoglobin, high-density lipoprotein-cholesterol, and waist-to-hip ratio.. OPG mRNA levels were associated with surrogate markers of insulin resistance in Egyptian obese women.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 2; Egypt; Female; Gene Expression Regulation; Humans; Insulin Resistance; Middle Aged; Obesity; Osteoprotegerin

The musculoskeletal system consisting of bones and muscles have been recognized as endocrine organs secreting hormones that are involved in regulating metabolic and inflammatory pathways. Obesity and type 2 diabetes (T2D) are associated with several musculoskeletal system complications. We hypothesized that an interaction exists between adipomyokines namely, irisin and METRNL, and various molecules involved in bone remodeling in individuals with obesity and T2D. A total of 228 individuals were enrolled in this study, including 124 non-diabetic (ND) and 104 T2D. A Multiplex assay was used to assess the level of various osteogenic molecules namely osteoactivin, Syndecan, osteoprotegerin (OPG) and osteonectin/SPARC. Our data shows elevated levels of Osteoactivin, Syndecan, OPG and SPARC in T2D as compared to ND individuals (p ≤ 0.05). Using Spearman's correlation, a positive correlation was observed between irisin and Osteoactivin as well as OPG (p < 0.05). Similarly, a positive association was observed between METRNL and Osteoactivin (p < 0.05). The strong positive association shown in this study between irisin, METRNL and various molecules with osteogenic properties emphasize a possible interaction between these organs. This report suggests that having a dysregulation in the level of the aforementioned molecules could potentially affect the development of bone and muscle related complications that are associated with obesity and T2D.

Topics: Adipokines; Adult; Bone Remodeling; Diabetes Mellitus, Type 2; Female; Fibronectins; Humans; Male; Membrane Glycoproteins; Middle Aged; Obesity; Osteogenesis; Osteonectin; Osteoprotegerin; Syndecan-4

A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis.. Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis.. A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011).. Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

Topics: Adaptor Proteins, Signal Transducing; Aged; Atherosclerosis; Biomarkers; Female; Glucuronidase; Humans; Klotho Proteins; Male; Middle Aged; Obesity; Osteopontin; Osteoprotegerin; Overweight

The receptor activator of nuclear factor-κB (NF-κB) (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG) are a triad of proteins that regulate bone metabolism, and serum OPG is considered a biomarker for cardiovascular diseases and Type 2 diabetes; however, the implications of OPG in adipose tissue metabolism remains elusive. In this study, we investigate RANK-RANKL-OPG signaling in white adipose tissue browning. Histological analysis of osteoprotegerin knockout (OPG-/-) mice showed subcutaneous white adipose tissue (sWAT) browning, resistance for high-fat diet-induced weight gain, and preserved glucose metabolism compared with wild-type (WT) mice. Stromal vascular fraction (SVF) cells from sWAT of OPG-/- mice showed multilocular morphology and higher expression of brown adipocyte marker genes compared with those from the WT group. Infusion of RANKL induced browning and elevated respiratory rates in sWAT, along with increased whole body oxygen consumption in mice measured by indirect calorimetry. Subcutaneous WAT-derived SVF and 3T3-L1 cells, but not mature white adipocytes, differentiated into beige adipose tissue in the presence of RANKL. Moreover, SVF cells, even under white adipocyte differentiation, showed multilocular lipid droplet, lower lipid content, and increased expression of beige adipocyte markers with RANKL stimulation. In this study, we show for the first time the contribution of RANKL to increase energy expenditure by inducing beige adipocyte differentiation in preadipocytes.

Topics: 3T3-L1 Cells; Adipocytes, Beige; Adipocytes, White; Adipogenesis; Adipose Tissue, Beige; Adipose Tissue, White; Animals; Calorimetry, Indirect; Diet, High-Fat; Energy Metabolism; Lipid Droplets; Mice; Mice, Knockout; Obesity; Osteoprotegerin; Oxygen Consumption; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Subcutaneous Fat; Weight Gain

Obesity and latent inflammation can give rise to insulin resistance and type 2 diabetes. Here we established an insulin resistance model of osteoblasts to explore the restoration effect of anti-inflammatory interleukin-4 (IL-4) on insulin sensitivity and its mechanism. We found that IL-4 inhibited cell proliferation in a concentration- and time-dependent manner. Insulation resistance significantly reduced the phosphorylation levels of the insulin receptor substrate 1 (IRS1; Tyr612), Akt (Ser473), and AS160 (Ser318) proteins. The addition of IL-4 to the insulin resistance model led to a dose-dependent stimulation of the phosphorylation of IRS1, Akt, and AS160. IL-4 fully restored the activation of the insulin cascade in insulin-resistant cells at the concentration of 50 ng/ml. Additionally, IL-4 promoted the expression of IRS1 in a time-dependent manner. We conjecture that IL-4 restores insulin sensitivity in osteoblasts by upregulating the expression of IRS1. It was also found that IL-4 promoted the expression of osteoprotegerin depending on the time of exposure. This effect may play an important role in the regulation of the energy metabolism in the whole body.

Topics: Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Energy Metabolism; Gene Expression Regulation; Humans; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-4; Lipids; Obesity; Osteoblasts; Osteoprotegerin; Phosphorylation

To investigate the relationship between osteocalcin and osteoprotegerin as bone markers and inflammatory biomarkers such as adiponectin, leptin, tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in children with nonalcoholic fatty liver disease (NAFLD).. This study included 40 obese children with NAFLD as the patient group and 40 healthy obese children of matched age, sex and BMI as the control group. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose, fasting insulin, Homeostatic model assessment method of insulin resistance (HOMA-IR), lipid profile, osteocalcin, osteoprotegerin, adiponectin, leptin, TNF-α, and IL-6 were measured in all participants.. Children with NAFLD had a significant decrease in osteocalcin, osteoprotegerin and adiponectin level with a significant increase in TNF-α and IL-6 levels. We also found a significant positive correlation between osteocalcin level and adiponectin levels but a significant negative correlation of osteocalcin with each of leptin and TNF-α. However, there was a significant negative correlation between osteoprotegerin levels and both TNF-α and IL-6 levels. Moreover, adiponectin and TNF-α were significant predictors for osteocalcin, and IL-6 was a significant predictor for osteoprotegerin.. Adiponectin, leptin, TNF-α, and IL-6 have potential association with the changes of osteocalcin and osteoprotegerin levels in children with NAFLD.

Topics: Adipokines; Adiponectin; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Blood Glucose; Body Mass Index; Case-Control Studies; Child; Cytokines; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Male; Non-alcoholic Fatty Liver Disease; Obesity; Osteocalcin; Osteoprotegerin; Tumor Necrosis Factor-alpha

Receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) axis has been hypothesized as a potential mediator of left ventricular hypertrophy (LVH). The aim of the study was to assess whether circulating concentrations of RANKL, RANK, and OPG were associated with early signs of morphological cardiac changes in overweight/obese youths.. We determined serum levels of RANKL, RANK and OPG by enzyme-linked immunosorbent assays in 188 overweight/obese children and adolescents. LV mass index (LVMI) and relative wall thickness (RWT) were estimated using M-mode echocardiography.. OPG and RANKL levels were higher among girls than among boys [1.73 (1.64-1.86) and 3.28 (1.90-6.37) pmol/L, respectively, vs. 1.69 (1.59-1.82) and 2.12 (1.52-3.80) pmol/L; p = 0.02 and p = 0.0001, respectively], but the OPG/RANKL ratio was lower [0.52 (0.26-0.88) vs 0.77 (0.44-1.11); p = 0.001]. In gender-specific multivariate linear regression, OPG/RANKL ratio was associated with LVMI and RWT in boys but not in girls. In multiple logistic regression, after adjustment for clinical variables, OPG/RANKL ratio was associated with concentric remodeling, eccentric and concentric LVH in boys but not in girls.. OPG/RANKL ratio is independently associated with LVH and patterns of LV structural remodeling in male overweight/obese children and adolescents.

Topics: Adolescent; Biomarkers; Child; Female; Humans; Hypertrophy, Left Ventricular; Male; Obesity; Osteoprotegerin; Overweight; Prognosis; RANK Ligand; Sex Factors

Sclerostin, osteoprotegerin, and bone-specific alkaline phosphatase (B-ALP), which are primarily related to bone metabolism, have been linked with insulin resistance in adults. We aimed to evaluate the association of these markers with growth, obesity, and parameters of insulin resistance in lean and obese children and adolescents.. We measured sclerostin, osteoprotegerin, and B-ALP in fasting and oral glucose tolerance test (oGTT) serum samples from 1,325 children and adolescents, and during 24-h profiles and after exercise and glucose exposure in young adults.. In addition to the positive relationship with height standard deviation scores (SDS), sclerostin (r = 0.035, p < 0.001) and B-ALP (r = 0.06, p = 0.028) increased, whereas osteoprotegerin (r = -0.098, p < 0.001) decreased with BMI SDS. Furthermore, B-ALP correlated with fasting- and oGTT-derived markers of glucose and insulin metabolism suggestive of insulin resistance. To evaluate potential confounding diurnal variation of bone markers, we performed 24-h profiles. B-ALP and osteoprotegerin had lower night-time levels. Exercise acutely and transiently increased B-ALP and osteoprotegerin levels, but glucose ingestion had no effect.. Besides their association with growth, sclerostin and osteoprotegerin levels are altered in childhood obesity. Particularly B-ALP was related to insulin resistance indices. Our findings accent the link between bone, growth, and insulin resistance.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adolescent Development; Alkaline Phosphatase; Biomarkers; Bone Morphogenetic Proteins; Child; Child Development; Child, Preschool; Female; Genetic Markers; Humans; Infant; Insulin Resistance; Male; Obesity; Osteoprotegerin

The role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (C) AIN93 M diet or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The two groups presented weight gain, but it was higher in the HFHS group compared to the C group (+35%, P = 0.0001). The HFHS group also had increased epididymal, inguinal and retroperitoneal fat pad weight (+121%, P = 0.0006; +287%, P = 0.0007 and; +286%, P < 0.0001, respectively), and hyperglycemia (+43%, P = 0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2, and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Kidney; Male; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Previous cross-sectional studies have established that circulating osteoprotegerin (OPG) levels are associated with nonalcoholic fatty liver disease (NAFLD). However, the role of OPG in metabolic diseases, such as diabetes and NAFLD, is still unclear. In the current study, we demonstrated that hepatic OPG expression was downregulated in NAFLD individuals and in obese mice. OPG deficiency decreased lipid accumulation and expression of CD36 and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the livers of OPG

Topics: Animals; CD36 Antigens; Extracellular Signal-Regulated MAP Kinases; Fatty Liver; Hepatocytes; Humans; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; Phosphorylation; PPAR gamma; Signal Transduction

Obesity is a complex disorder that is influenced by genetic and environmental factors. DNA methylation is an epigenetic mechanism that is involved in development of obesity and its metabolic complications. The aim of this study was to investigate the association between the RANKL and c-Fos gene methylation on obesity with body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), plasma leptin, adiponectin and resistin levels. The study included 68 obese and 46 non-obese subjects. Anthropometric parameters, including body weight, body mass index, waist circumference, and waist-hip ratio, were assessed. Serum glucose, triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), plasma leptin, adiponectin and resistin levels were measured. Methylation status of RANKL and c-Fos gen were evaluated by MS-HRM. Statistically significant differences were observed between obese patients and the controls with respect to RANKL and c-Fos gene methylation status (p < 0.001). Also, statistically significant importance was observed RANKL gene methylation and increased level of leptin in obese subjects (p = 0.0081). At the same time, statistically significant association between methylation of c-Fos and increased level of adiponectin was observed in obese patients (p = 0.03) On the other hand, decreased level of resistin was observed where the c-Fos was unmetyladed in controls (p = 0.01). We conclude that methylation of RANKL and c-Fos genes have significant influences on obesity and adipokine levels. Based on literature this was the first study which shows the interactions between RANKL and c-Fos methylation and obesity.

Topics: Adiponectin; Adult; Anthropometry; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation; Genes, fos; Humans; Insulin Resistance; Leptin; Male; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Triglycerides

This study assessed the influence of obesity on the progression of ligature-induced periodontitis in rats.. Forty-eight adult Wistar rats were randomly divided into two groups: the HL group (n = 24) was fed high-fat animal food to induce obesity, and the NL group (n = 24) was fed normolipidic animal food. Obesity was induced within a period of 120 days, and the induction of experimental periodontitis (EP) was subsequently performed for 30 days. The animals were euthanized after 7, 15, and 30 days, and the jaws were removed for histopathological, histometric, and immunohistochemical analyses. Tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear factor kappa beta ligand (RANKL), and osteoprotegerin (OPG) were analyzed via immunolabeling.. Histological findings indicated that the inflammation was more extensive and lasted longer in the HL⁄EP; however, advanced destruction also occurred in the NL/EP. Greater bone loss was verified in the HL/EP group (2.28 ± 0.35) in the period of 7 days than in the NL/EP group (1.2 ± 0.29). High immunolabeling was identified in the HL/EP group in the initial periods for RANKL and TRAP, whereas the NL⁄EP group presented with moderate immunolabeling for both factors. The HL/EP and NL/EP groups showed low immunolabeling for OPG.. Obesity induced by a high-fat diet influenced alveolar bone metabolism when associated with experimental periodontitis and caused a more severe local inflammatory response and alveolar bone loss.. Obesity is related to greater alveolar bone loss and an accentuated local inflammatory response, which may be reflected in the clinical severity of periodontitis and dental loss.

Topics: Alveolar Bone Loss; Animals; Immunohistochemistry; Male; Obesity; Osteoprotegerin; Periodontitis; Random Allocation; RANK Ligand; Rats; Rats, Wistar; Tartrate-Resistant Acid Phosphatase

Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P

Topics: Adipocytes; Adipose Tissue; Aldehyde-Lyases; Anabolic Agents; Animals; Bone Resorption; Cell Differentiation; Cell Line; Femur; Gene Deletion; Lysophospholipids; Mice, Knockout; Molecular Targeted Therapy; Obesity; Organ Size; Osteoblasts; Osteoclasts; Osteoporosis; Osteoprotegerin; PPAR gamma; Signal Transduction; Sp7 Transcription Factor; Sphingosine; X-Ray Microtomography

BACKGROUND Osteoprotegerin (OPG) is a soluble glycoprotein that belongs to the tumor necrosis factor (TNF) receptor superfamily. OPG is mainly secreted by bone. The relationship between acute resistance training, serum OPG levels and metabolic syndrome, including insulin resistance, remains unclear. The purpose of this study was to determine the effect of resistance exercise on serum OPG levels and insulin resistance in middle-aged women with metabolic syndrome. MATERIAL AND METHODS Twenty-four middle-aged women were divided into those with metabolic syndrome (n=12) and a normal control group without metabolic syndrome or insulin resistance (n=12). Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria. The quantitative insulin-sensitivity check index (QUICKI) and the homeostatic model assessment (HOMA) index for assessing beta-cell function and insulin resistance were used. The intensity of the resistance exercise was 60-70% of the repetition maximum, for 40 minutes with 10-12 repetitions, performed three times per week. Venous blood samples were tested using standard laboratory procedures. RESULTS Before exercise, the metabolic syndrome group showed a significant increase in waist circumference (P=0.030) and serum triglyceride (TG) (P=0.014), and lower high-density lipoprotein-cholesterol (HDL-C) (P=0.010) compared with the control group. After the eight-week resistance exercise program, waist circumference, and the QUICKI decreased and OPG levels were significantly increased in the metabolic syndrome group compared with the normal control group. CONCLUSIONS A resistance exercise program was effective in reducing factors associated with metabolic syndrome including insulin resistance and increases serum levels of OPG in middle-aged women.

Topics: Blood Glucose; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Exercise; Exercise Therapy; Female; Humans; Insulin Resistance; Metabolic Syndrome; Middle Aged; Obesity; Osteoprotegerin; Resistance Training; Triglycerides; Waist Circumference

The relationship between obesity and bone tissue remains contradictory, especially when the effect of high-fat diet is assessed in experimental models. The aim of this study was to evaluate the effects of high-fat diet on bone metabolism of growing rats.. Twenty weaned female Wistar rats were equally divided into two groups: SD (standard diet) and HFD (high-fat diet with 60 % of energy as fat). After five weeks of the two diets, the rats were euthanized, and the liver, blood and bones extracted. The liver was analysed for malondialdehyde (MDA) and reduced glutathione (GSH) concentrations. Blood was analysed by the ELISA method for osteoprotegerin (OPG) and tumour necrosis factor ligand superfamily member 11 (TNFSF11/RANKL). The bone tissue was analysed by dual-energy X-ray absorptiometry (DXA), mechanical tests, computed microtomography, histological quantitative analysis and scanning electron microscopy. The gene expressions of PPAR-γ Runx-2, RANKL and Cathepsin-K were also evaluated.. HFD caused an increase in the MDA concentration, indicating oxidative stress. It also increased the expression of PPAR-γ, which is the gene that is related to adipocyte differentiation. There was an increase in BMD of the tibia of animals fed with the HFD, but other microstructural and mechanical properties were maintained unaltered. In addition, there were no changes in the gene expressions related to the differentiation of osteoblasts and osteoclasts, as well as no changes to the biochemical markers of bone formation and bone resorption.. Liver and gene parameters are changed in response to the HFD. However, although there was an increase in BMD, the microstructure and function of the bone did not change after a 5-week HFD.

Topics: Absorptiometry, Photon; Adipocytes; Animals; Bone and Bones; Bone Density; Bone Resorption; Cathepsin K; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Diet, High-Fat; Female; Glutathione; Growth; Liver; Malondialdehyde; Obesity; Osteoblasts; Osteoclasts; Osteoprotegerin; PPAR gamma; RANK Ligand; Rats; Rats, Wistar; Tibia

Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and in the actions of peroxisome proliferator-activated receptor (PPAR) α and γ in mice. We have conducted independent studies to examine the effects of FGF21 on bone homeostasis and the role of FGF21 in PPARα and γ actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human FGF21 (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, and 3 mg/kg daily for 2 weeks. Additional groups of DIO mice received water or 10 mg/kg rosiglitazone daily. Mice treated with rhFGF21 or rosiglitazone showed expected metabolic improvements in glucose, insulin, and lipid levels. However, bone loss was not detected in rhFGF21-treated mice by dual-energy X-ray absorptiometry (DXA), micro-CT, and histomorphometric analyses. Mineral apposition rate, a key bone formation parameter, was unchanged by rhFGF21, while significantly decreased by rosiglitazone in DIO mice. Bone resorption markers, OPG/RANKL mRNA expression, and histological bone resorption indices were unchanged by rhFGF21 or rosiglitazone. Bone marrow fat was unchanged by rhFGF21, while increased by rosiglitazone. Furthermore, FGF21 knockout mice did not show high bone mass phenotype. Treatment with PPARα or PPARγ agonists caused similar metabolic effects in FGF21 knockout and wild-type mice. These results contrast with previous findings and suggest that FGF21 is not critical for bone homeostasis or actions of PPARα and PPARγ. © 2016 American Society for Bone and Mineral Research.

Topics: Animals; Bone Density; Dietary Fats; Fibroblast Growth Factors; Gene Expression Regulation; Glucose; Homeostasis; Humans; Insulin; Male; Mice; Mice, Knockout; Obesity; Osteoprotegerin; PPAR alpha; PPAR gamma; RANK Ligand; Rosiglitazone; Thiazolidinediones

Bariatric surgery has been associated with bone remodeling changes. The action of adipokines on the expression of receptor activator of nuclear factor kappa β ligand (RANKL) and osteoprotegerin (OPG) and on an increase in sclerostin could be related to these changes.. This study aimed to assess the repercussions of weight loss, fat mass (FM), and fat-free mass (FFM) loss and biochemical and hormonal changes on bone remodeling markers after Roux-en-Y gastric bypass (RYGB). Anthropometric data, parathyroid hormone (PTH), bone-specific alkaline phosphatase (BSAP), collagen type 1 C-telopeptide (CTX), 25-hydroxy vitamin D (25-OH-VitD), leptin, adiponectin, RANKL, OPG, and sclerostin of 30 menstruating women were measured preoperatively (Pre), and 3, 12, and 24 months (m) after RYGB.. Leptin (34.4 (14.7; 51.9) vs. 22.5 (1.9; 52.7) ng/mL) and OPG (3.6 (1.1; 11.5) vs. 3.4 (1.5; 6) pmol/L) decreased, and adiponectin (7.4 (1.7; 18.4) vs. 13.8 (3.0; 34.6) μg/mL), CTX (0.2 (0.1; 2.2) vs. 0.6 (0.4; 6.0) ng/mL), RANKL (0.1 (0.0; 0.5) vs. 0.3 (0.0; 2.0) pmol/L), and sclerostin (21.7 (3.2; 75.1) vs. 34.8 (6.4; 80.5) pmol/L) increased after 3 m. BSAP increased after 12 m (10.1 (5.4; 18.9) vs. 13.9 (6.9; 30.2) μg/mL) (p < 0.005). CTX correlated positively with adiponectin at 24 m and inversely with leptin Pre; OPG at 3 m; weight, FM, FFM, and leptin at 24 m. RANKL correlated directly with weight at 3 m. Sclerostin correlated inversely with weight Pre and FM at 3 m. BSAP correlated negatively with 25-OH-VitD at 12 m, and positively with PTH at 24 m.. RYGB induced weight loss, and biochemical, hormonal, and body composition changes are associated with higher bone remodeling.

Topics: Adaptor Proteins, Signal Transducing; Adipocytes; Adipokines; Adult; Anthropometry; Biomarkers; Bone Morphogenetic Proteins; Bone Remodeling; Female; Gastric Bypass; Genetic Markers; Humans; Middle Aged; Obesity; Osteoprotegerin; Prospective Studies; RANK Ligand; Weight Loss; Young Adult

This study evaluates the effect of isoflavone cladrin on high-fat diet (HFD)-induced bone loss and adipogenesis.. Thirty-two 4-week-old male C57BL/6J mice were divided into four groups: a standard diet group, a HFD group and HFD group with cladrin (5 and 10 mg/kg per day orally) for 12 weeks. The effect of cladrin on bone micro-architecture, bone marrow cell lineages and hyperlipidaemia were assessed. For assessing anti-adipogenic activity of cladrin, 3T3-L1 cells were used.. Cladrin attenuated HFD-induced hyperlipidaemia and bone loss by preserving bone micro-architecture and strength. Effect of cladrin was found at the level of bone marrow progenitor cells. Gene expression profile of cladrin-treated mice bone showed upregulation of osteoblast and downregulation of adipogenic transcription factors and increased OPG/RANKL ratio. Cladrin inhibited cellular lipid accumulation through downregulation of transcription factors such as PPAR-γ and C/EBP-α and modulated the expression of major adipokines involved behind obesity stimulation without eliciting cell cytotoxicity in 3T3-L1 adipocytes.. We conclude that cladrin may improve obesity-induced bone loss and hyperlipidaemia in mice fed HFD and adipogenesis in 3T3-L1 cells by modifying adipokines and could offer clinical benefits as a supplement to treat obesity-induced disorders.

Topics: 3T3-L1 Cells; Adipogenesis; Adipokines; Adipose Tissue; Animals; Bone and Bones; Butea; Diet, High-Fat; Isoflavones; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoporosis; Osteoprotegerin; Phytoestrogens; Phytotherapy; Plant Extracts; RANK Ligand; Transcription Factors

To investigate the relationships of osteoprotegerin (OPG) concentrations to brachial artery flow-mediated vasodilation (FMD) and the carotid artery intima media thickness (CIMT) in polycystic ovary syndrome (PCOS).. Thirty-seven women with PCOS and 41 controls matched for body mass index (BMI) and age were included in study. The serum OPG concentrations, hormonal and metabolic profiles were measured in women with PCOS and in control group. The CIMT and brachial artery FMD were evaluated in both groups.. The mean serum concentrations of all hormones were comparable, except LH, which was higher in women with PCOS. Lipid parameters were similar between groups. There were no differences between groups with respect to fasting glucose, 2-h glucose, fasting insulin, HbA1c and HOMA-IR. The mean osteoprotogerin concentrations were higher in PCOS group (11.39 ± 2.29 vs. 10.22 ± 2.25 pmol/L, P = 0.026). The mean CIMT was higher in PCOS group than control group (0.52 ± 0.058 vs. 0.45 ± 0.059 mm, P < 0.01). The mean brachial artery FMD was lower in PCOS group (0.068 ± 0.022 vs. 0.055 ± 0.029, P = 0.017).. We found high osteoprotogerin concentrations, increased CIMT and decreased FMD, in women with PCOS. However, there was no correlation between osteoprotegerin and cardiovascular risk markers.

Topics: Adult; Body Mass Index; Brachial Artery; Cardiovascular Diseases; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Endothelium, Vascular; Female; Humans; Lipids; Obesity; Osteoprotegerin; Polycystic Ovary Syndrome; Risk Factors; Vasodilation

A number of unexpected molecules were recently identified as products of osteoblasts, linking bone homeostasis to systemic energy metabolism. Here we identify the lipolytic enzyme hepatic lipase (HL, encoded by Lipc) as a novel cell-autonomous regulator of osteoblast function. In an unbiased genome-wide expression analysis, we find Lipc to be highly induced upon osteoblast differentiation, verified by quantitative Taqman analyses of primary osteoblasts in vitro and of bone samples in vivo. Functionally, loss of HL in vitro leads to increased expression and secretion of osteoprotegerin (OPG), while expression of some osteoblast differentiation makers is impaired. When challenging energy metabolism in a diet-induced obesity (DIO) study, lack of HL leads to a significant increase in bone formation markers and a decrease in bone resorption markers. Accordingly, in the DIO setting, we observe in Lipc(-/-) animals but not in wild-type controls a significant increase in lumbar vertebral trabecular bone mass and formation rate as well as in femoral trabecular bone mass and cortical thickness. Taken together, we demonstrate that HL expressed by osteoblasts has an impact on osteoblast OPG expression and that lack of HL leads to increased bone mass in DIO. These data provide a novel and completely unexpected molecular link in the complex interplay of osteoblasts and systemic energy metabolism.

Topics: Animals; Biomarkers; Bone Remodeling; Cell Differentiation; Cells, Cultured; Diet, High-Fat; Feeding Behavior; Femur; Lipase; Lumbar Vertebrae; Male; Mice, Inbred C57BL; Obesity; Organ Size; Osteoblasts; Osteoprotegerin; X-Ray Microtomography

Inflammation is believed to link obesity to insulin resistance, as in the setting of metabolic syndrome (MetS). Osteoprotegerin (OPG) is a soluble protein that seems to exert proatherogenic and prodiabetogenic effects. This study aims at determining OPG levels in MetS and whether OPG might contribute to MetS development and progression.. Circulating OPG was measured in 46 patients with MetS and 63 controls, and was found significantly elevated in those with MetS. In addition, circulating and tissue OPG was significantly increased in high-fat diet (HFD) fed C57BL6 mice, which is one of the animal models for the study of MetS. To evaluate the consequences of OPG elevation, we delivered this protein to C57BL6 mice, finding that it promoted systemic and adipose tissue proinflammatory changes in association with metabolic abnormalities.. These data suggest that OPG may trigger adipose tissue proinflammatory changes in MetS/HFD-induced obesity.

Topics: Adipose Tissue; Adult; Animals; Blood Glucose; Body Mass Index; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Female; Humans; Inflammation; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Middle Aged; Obesity; Osteoprotegerin; Triglycerides

It has been suggested that changes in the production of adipose tissue hormones in obese postmenopausal women might affect their bone status. The aim of this study was to determine whether obese postmenopausal women exhibited any relationship between serum levels of LP, ADIPO, RES, VISF, APE and bone metabolism markers (OC and CTx), OPG, sRANKL, the OPG/sRANKL ratio as well as BMD.. 80 postmenopausal women (60 obese and 20 healthy) underwent BMD measurement using dual-energy X-ray absorptiometry (DXA) at lumbar spine L2-L4. Serum levels of selected adipose tissue hormones, OC, CTx, OPG and its soluble ligand, sRANKL, were assessed by ELISA.. Obese postmenopausal women demonstrated a significant increase in body mass, BMI and WHR associated with significant increases in LP and RES levels, a decrease in ADIPO concentration, suppression of OC, CTx, OPG and sRANKL and an increase in the OPG/sRANKL ratio and BMD. BMI correlated positively with BMD, LP, RES, OPG and the OPG/sRANKL ratio, whereas in the case of ADIPO, OC, CTx, sRANKL the relationship was negative. WHR was positively correlated with the OPG/sRANKL ratio, and negatively with ADIPO and APE. A positive correlation was found between BMD and LP, APE and the OPG/sRANKL ratio, while the correlation between BMD and ADIPO, CTx, sRANKL was negative. Significant positive correlations were also revealed between OC, CTx and ADIPO; OPG and ADIPO; sRANKL and ADIPO, RES; the OPG/sRANKL ratio and LP. OC correlated negatively with LP, RES, VISF, APE; CTx with LP, VISF, APE; OPG with LP; sRANKL with LP and APE; the OPG/sRANKL ratio with VISF. ADIPO was an independent predictor of OC, OPG and sRANKL, while LP turned out to be an independent predictor of CTx, OPG, sRANKL and the OPG/sRANKL ratio.. Obesity in postmenopausal women can lead to changes in BMD, circulating levels of bone markers, OPG, sRANKL and/or the OPG/sRANKL ratio; these changes are associated with alterations in the concentrations of adipose tissue hormones under investigation. The relationships between bone status indicators and adipose tissue hormones, especially LP and ADIPO, seem to suggest that changes in these hormones observed in obese postmenopausal women might have a protective effect on bone tissue, most probably via a shift in the OPG/sRANKL ratio towards a functional excess of OPG.

Topics: Adipose Tissue; Biomarkers; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Female; Humans; Middle Aged; Obesity; Osteoprotegerin; Postmenopause; RANK Ligand

Some data indicate a potential relationship between insulin resistance level and the concentration of osteoprotegerin (OPG) in the body. There have been few studies concerning OPG level and its relationship with insulin resistance and body composition in young people. The aim of this study was to assess serum osteoprotegerin concentration in obese adolescents, and to evaluate its potential association with insulin resistance. Seventy-eight obese adolescents and 20 healthy volunteers aged 12-18 years were recruited in the study. Selected anthropometrical measurements and blood biochemical analyses were performed. Insulin resistance in the participants was evaluated according to the homeostasis model assessment-insulin resistance (HOMA-IR) protocol. Level of OPG was assessed in serum. Obese subjects had significantly higher HOMA-IR indices and OPG levels in serum than the control group. A significant positive correlation between OPG and insulin resistance was found. It was observed that high concentrations of osteoprotegerin are associated with insulin resistance in obese adolescents.

Topics: Adolescent; Blood Glucose; Body Composition; Body Mass Index; Case-Control Studies; Child; Female; Gene Expression; Humans; Insulin; Insulin Resistance; Male; Obesity; Osteoprotegerin

Obesity is markedly associated with abnormal bone density indicating the importance of adipocytes in bone metabolism. However, the specific function of adipocytes remains unclear, with marked discrepancies in observations of previous studies. In the present study, the effect of adipocytes on osteoblasts/osteoclasts was analyzed. A mouse model of obesity was established and an in vitro co-culture system was utilized containing adipocyte and MC3T3/RAW 264.7 cells in a Transwell plate. Compared with control mice, obese mice exhibited low body weight and bone mineral density of the tibia and fat cells were observed to accumulate in bone marrow. MC3T3/RAW 264.7 cells were co-cultured with adipocytes and the mRNA and protein expression of alkaline phosphatase and osteocalcin was found to be decreased in MC3T3-E1 cells and mRNA and protein expression of tartrate-resistant acid phosphatase and cathepsin K was significantly increased in RAW 264.7 cells. In addition, the effect of adipocytes on the osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL)/RANK system indicated that the RANKL/OPG ratio secreted by osteoblasts increased and RANK expression by osteoclasts increased, leading to increased osteoclastogenesis. These results indicate that bone metabolism is impaired in obese mice leading to decreased osteoblastogenesis and marked increases in osteoclastogenesis and low bone mass.

Topics: Acid Phosphatase; Adipocytes; Alkaline Phosphatase; Animals; Bone Density; Bone Marrow Cells; Cathepsin K; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Osteocalcin; Osteogenesis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the "prediabetic" state, urging the development of diagnostic tests to recognize the group at risk in time.. The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes.. Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated.. Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives.. These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically susceptible females.. Bevezetés: A 2-es típusú cukorbetegség ma már „világjárvány”, megelőzése csak a „praediabetes” idején eredményes, ezért olyan szűrővizsgálatokra van szükség, amelyek a cukorbetegség várományosait időben felfedik. Célkitűzés: A szerzők célul tűzték ki egészséges, negatív családi anamnézisű (genetikailag nem diabeteses) és elsőfokú cukorbeteg rokonokkal rendelkező (genetikailag diabeteses), normális szénhidrát-toleranciájú és inzulinérzékenységű nőkben a diagnosztikai értékű anyagcsere-eltérések feltárását. Módszer: A klemp vizsgálatok során normális inzulinérzékenységű, genetikailag nem diabeteses (n = 26) és genetikailag diabeteses (n = 18) önkéntesek adatait elemezték. Eredmények: Genetikailag diabeteses, egészséges nőkben az orális cukorterhelés 120. percében magasabb glükóz- és inzulinkoncentrációt, valamint nagyobb magas denzitású és kisebb alacsony denzitású lipidszintet találtak a genetikailag nem diabeteses egészséges nőkben mért értékekhez képest. Következtetések: Az eredmények szerint genetikailag diabeteses, egészséges nőkben a kialakuló inzulinrezisztenciát megelőzi a hepaticus inzulinrezisztencia és a zsíranyagcsere zavara. A szerzők nem kaptak választ arra a kérdésre, hogy a cukorbetegséghez és az elhízáshoz vezető energiafelesleg miért okoz genetikailag diabeteses nőkben korán zsíranyagcsere-zavart és hyperinsulinaemiát, továbbá arra sem, hogy az elhízás miért nem társul mindig inzulinrezisztenciával. Orv. Hetil., 2013, 154, 1747–1753.

Topics: Adipokines; Adult; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Family; Female; Follicle Stimulating Hormone; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Interleukin-6; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Obesity; Osteocalcin; Osteoprotegerin; Prediabetic State; Triglycerides; Tumor Necrosis Factor-alpha

Biomarkers of cardiovascular (CV) risk are tests that predict a patient's risk of future CV events. Recently, two proteins involved in vascular calcification; serum levels of osteoprotegerin (OPG) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) have emerged as potentially useful biomarkers. OPG levels are positively correlated with CV risk, whereas TRAIL levels show a negative correlation. Exercise training is known to reduce risk factors for CV disease by improving metabolism, vascular biology and blood flow. This study examined the effects of a 6-month exercise training programme on levels of OPG and TRAIL. Pulse wave velocity (PWV) and high-sensitivity C-reactive protein (hsCRP) were measured for comparative purposes.. Overweight and obese patients undertook a 6-month exercise programme. Patients participated in 4 h of primarily aerobic exercise per week of which 2 h were supervised. At the beginning and end of the programme, anthropometric measurements, PWV and serum levels of OPG, TRAIL and hsCRP were measured.. A total of 21 patients (17 men) aged 55.2 ± 10 years completed the programme. Mean body mass index decreased from 34.1 ± 5.8 to 32.6 ± 5.4 kg/m(2) (P<0.05), while waist circumference decreased from 111.8 ± 12.4 to 109.6 ± 12.8 cm (P<0.05). PWV decreased from 9.2 to 8.5 m/s (P<0.02). OPG, TRAIL and hsCRP levels did not change significantly.. Exercise training reduced PWV but not OPG, TRAIL or hsCRP in this population. These data suggest that while an intervention of this nature improves vascular tone, it does not exert significant effects on serum biomarkers related to atherosclerotic inflammation and calcification.

Topics: Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Exercise; Female; Humans; Male; Middle Aged; Obesity; Osteoprotegerin; Pulse Wave Analysis; Risk Factors; TNF-Related Apoptosis-Inducing Ligand; Waist Circumference

Clinical evidence indicates that fat is inversely proportional to bone mass in elderly obese women. However, it remains unclear whether obesity accelerates bone loss. In this report we present evidence that increased visceral fat leads to inflammation and subsequent bone loss in 12-month-old C57BL/6J mice that were fed 10% corn oil (CO)-based diet and a control lab chow (LC) for 6 months. As expected from our previous work, CO-fed mice demonstrated increased visceral fat and enhanced total body fat mass compared to LC. The adipocyte-specific PPARγ and bone marrow (BM) adiposity were increased in CO-fed mice. In correlation with those modifications, inflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly elevated in CO-fed mice compared to LC-fed mice. This inflammatory BM microenvironment resulted in increased superoxide production in osteoclasts and undifferentiated BM cells. In CO-fed mice, the increased number of osteoclasts per trabecular bone length and the increased osteoclastogenesis assessed ex-vivo suggest that CO diet induces bone resorption. Additionally, the up-regulation of osteoclast-specific cathepsin k and RANKL expression and down-regulation of osteoblast-specific RUNX2/Cbfa1 supports this bone resorption in CO-fed mice. Also, CO-fed mice exhibited lower trabecular bone volume in the distal femoral metaphysis and had reduced OPG expression. Collectively, our results suggest that increased bone resorption in mice fed a CO-enriched diet is possibly due to increased inflammation mediated by the accumulation of adipocytes in the BM microenvironment. This inflammation may consequently increase osteoclastogenesis, while reducing osteoblast development in CO-fed mice.

Topics: Adipocytes; Animals; Biomarkers; Body Weight; Bone Marrow; Bone Resorption; Corn Oil; Dietary Fats; Female; Femur; Gene Expression; Intra-Abdominal Fat; Mice; Mice, Inbred C57BL; Obesity; Osteoblasts; Osteoclasts; Osteoprotegerin; PPAR gamma; RANK Ligand

Obese children, particularly those who have fractured, have reduced body size-adjusted total body and regional bone mass. We performed an observational cross-sectional cohort study to determine the relationship between adipokines (leptin and adiponectin), bone-derived cytokines and bone turnover in children which may explain this observation. Participants aged 5-16 years were recruited into obese (BMI SDS 3.3±0.6) and lean (BMI SDS 0.2±1.0) groups and further subdivided into groups by fracture history. Free leptin (leptin/leptin soluble receptor) and adiponectin; RANK-ligand (RANKL), osteoprotegerin (OPG); Dickkopf-1 (DKK1); and the bone turnover markers procollagen type I amino propeptide (P1NP) and carboxy-terminal telopeptide of type I collagen (CTx). Total body and truncal fat mass were measured by DXA.. Free leptin (p>0.0001) and adiponectin (p=0.0002) were higher and lower in obese children respectively. OPG was lower in obese children (p=0.01), being inversely related to free leptin (p=0.009), total body and truncal fat mass (both p=0.01). RANKL was inversely related to free leptin in children with prior fracture (p=0.03). CTx was higher in obese children (p=0.003). Free leptin was positively associated with both CTx (p=0.03) and P1NP (p=0.02). DKK1 was inversely related to adiponectin (p=0.02).. Bone formation relative to resorption was reduced in obese children; this difference was accentuated in those with prior fracture. Adipokines may regulate these changes. Osteoprotegerin may play a fundamental role in the failure of obese children to accrue bone mass appropriately.

Topics: Adipokines; Adiponectin; Adolescent; Child; Child, Preschool; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Obesity; Osteoprotegerin; RANK Ligand

Osteoprotegerin (OPG), a novel soluble member of tumour necrosis factor receptor superfamily, has been shown to link cardiovascular disorders. The aim of this study is to investigate the potential relationship between serum OPG levels, cardiovascular risk factors and metabolic syndrome in a relatively large group of women with previous GDM. In this cross-sectional case-control study, 128 women with previous GDM and 67 age-matched controls were enrolled. Subjects were evaluated for the diagnosis of metabolic syndrome according to the criteria of the American Heart Association (AHA). Fasting glucose, insulin, serum lipids, CRP and OPG were assayed. HOMA score was calculated. Carotid intima media thickness (IMT) was measured. There was no significant increase in OPG levels in women with previous GDM when compared to controls. On the other hand, women with previous GDM developing metabolic syndrome had higher OPG levels than those without metabolic syndrome and healthy controls. Serum OPG levels were associated with obesity, insulin resistance, serum CRP and carotid IMT. Serum OPG is related to cardiovascular risk factors and metabolic syndrome, and might be involved in the development of cardiovascular disorders in women with previous GDM.

Topics: Adult; Atherosclerosis; C-Reactive Protein; Cardiovascular Diseases; Carotid Arteries; Case-Control Studies; Cross-Sectional Studies; Diabetes, Gestational; Female; Humans; Insulin Resistance; Metabolic Syndrome; Obesity; Osteoprotegerin; Pregnancy; Risk Factors; Tunica Intima; Tunica Media; Turkey; Ultrasonography

An increase in serum osteoprotegerin (OPG) is associated with type 2 diabetes mellitus, the severity of vascular calcification, and coronary artery disease. Obesity is a risk factor for diabetes and cardiovascular disease, but little is known about the relationship between OPG and obesity. The purpose of this study was to determine if changes in body mass index (BMI) and insulin sensitivity influence circulating OPG in healthy subjects. A total of 100 subjects (36 lean, 41 overweight, and 23 obese) with normal glucose tolerance, blood pressure, and electrocardiogram stress test result volunteered for this study. Insulin sensitivity was estimated using a 2-hour oral glucose tolerance test with oral glucose insulin sensitivity analysis. Osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),soluble receptor activator of nuclear factor-κβ ligand (sRANKL), and adiponectin were analyzed using commercially available enzyme-linked immunosorbent assays. Osteoprotegerin (P < .01) and adiponectin (P < .001) were significantly decreased in the obese compared with lean subjects. There was no significant difference between BMI categories for TRAIL or sRANKL. Controlling for age and sex, there was a significant correlation between OPG and adiponectin (r = 0.391, P < .001), BMI (r = -0.331, P < .001), waist circumference (r = -0.268, P < .01), homeostasis model assessment of insulin resistance (r = -0.222, P < .05), and oral glucose insulin sensitivity (r = 0.221, P < .05). Both OPG and adiponectin were negatively correlated with body weight, BMI, waist circumference, and fasting plasma insulin while being positively correlated with insulin sensitivity (P < .05). Controlling for age, sex, and BMI, TRAIL was positively related to fat mass (r = 0.373, P < .001) and waist circumference (r = 0.257, P < .05). In contrast to patients with type 2 diabetes mellitus, circulating OPG is lower in obese, but otherwise healthy subjects and is positively correlated with indices of insulin sensitivity.

Topics: Adiponectin; Adult; Blood Pressure; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand; Waist Circumference

It has been suggested that increased testosterone secretion in postmenopausal obese women might have some protective effect on bone tissue; the association might be significantly influenced by the RANKL/RANK/OPG system.. The aim of the study was to determine whether postmenopausal obese women showed any relationship between the pattern of adipose tissue distribution, circadian free testosterone (FT) concentrations and bone metabolism (as assessed based on circadian osteocalcin [OC] and C-terminal telopeptide [CTx] levels), and to establish whether osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) might play a role in the relationship.. FT, OC, CTx, OPG and soluble RANKL (sRANKL) levels were determined by ELISA in serum samples collected every three hours for 24 hours from 47 postmenopausal women (12 with gynoid obesity [GO], 17 with android obesity [AO], and 18 healthy individuals).. Obese women demonstrated an adipose tissue distribution-dependent increase in mean circadian FT levels and a decrease in mean circadian OC, CTx, OPG and sRANKL compared to control participants. In GO subjects, these changes were accompanied by smaller FT amplitudes, suppression of the circadian rhythms of bone markers and OPG, and a shift of sRANKL rhythm acrophase, whereas AO subjects showed a decrease in bone marker amplitudes and suppression of OPG and sRANKL rhythms. In comparison with the controls, significant adipose tissue distribution-dependent changes were found in the correlations between FT and bone markers, FT and OPG, OC and CTx, OPG and sRANKL, CTx and OPG, and CTx and sRANKL. Compared to GO participants, those with AO had higher coefficients of correlations between mean circadian FT and OC as well as between OC and CTx, and lower in the case of FT and sRANKL as well as CTx and OPG and CTx and sRANKL.. Postmenopausal obesity results in adipose tissue distribution-dependent alterations in circadian FT levels accompanied by suppression of bone metabolism and a decline in circadian variations of the osteokines under investigation, especially sRANKL. Increased FT secretion in postmenopausal women might exert a protective effect on bone tissue, most likely via a shift in the OPG/RANKL ratio that tilts the balance toward a functional excess of OPG.

Topics: Age Factors; Aged; Biomarkers; Bone and Bones; Bone Remodeling; Case-Control Studies; Circadian Clocks; Female; Humans; Middle Aged; Obesity; Osteoprotegerin; Postmenopause; RANK Ligand; Testosterone

Both physical activity and body mass affect bone properties. In this study we examined how diet-induced obesity combined with voluntary physical activity affects bone properties. Forty 7-week-old male C57BL/6J mice were assigned to four groups evenly: control diet (C), control diet + running (CR), high-fat diet (HF, 60% energy from fat), and high-fat diet + running (HFR). After 21-week intervention, all mice were killed and the left femur was dissected for pQCT and mechanical measurements. Body mass increased 80% in HF and 62% in HFR, with increased epididymal fat pad weight and impaired insulin sensitivity. Except for total and trabecular volumetric bone mineral density (BMD), bone traits correlated positively with body mass, fat pad, leptin, and osteoprotegerin. Obesity induced by a high-fat diet resulted in increased femoral bone cross-sectional area, mineral content (BMC), polar moment of inertia, and mechanical parameters. Of the mice accessing the running wheel, those fed the control diet had thinner cortex and less total metaphyseal BMC and BMD, with enlarged metaphyseal marrow cavity, whereas mice fed the high-fat diet had significantly higher trabecular BMD and smaller marrow cavity. However, the runners had a weaker femoral neck as indicated by decreased maximum flexure load. These results suggest that voluntary running exercise affects bone properties in a site-specific manner and that there is a complex interaction between physical activity and obesity. Thus, both diet and exercise should be considered when optimizing the effects on body composition and bone, even though the underlying mechanisms remain partly unknown.

Topics: Adipose Tissue; Animals; Biomarkers; Body Weight; Bone Density; Dietary Fats; Femur; Glucose Tolerance Test; Insulin; Insulin Secretion; Leptin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Osteocalcin; Osteoprotegerin; Physical Conditioning, Animal; Stress, Mechanical; Tomography, X-Ray Computed

Carboxypeptidase E (CPE) is a prohormone/proneuropeptide processing enzyme, and mice bearing CPE mutations exhibit an obese and diabetic phenotype. Studies on CPE knockout (KO) mice revealed poor prohormone processing, resulting in deficiencies in peptide hormones/neuropeptides such as insulin, gonadotropin-releasing hormone, and cocaine- and amphetamine-regulated transcript (CART). Here, we show that CPE KO mice, an obese animal model, have low bone mineral density (BMD) accompanied by elevated plasma CTX-1 (carboxy-terminal collagen crosslinks), and osteocalcin, indicators of increased bone turnover. Receptor activator for NF-kappaB ligand (RANKL) expression was elevated approximately 2-fold relative to osteoprotegerin in the femur of KO animals, suggesting increased osteoclastic activity in the KO mice. In the hypothalamus, mature CART, a peptide involved in eating behavior and implicated in bone metabolism, was undetectable. The melanocortin and neuropeptide Y (NPY) systems in the hypothalamus have also been implicated in bone remodeling, since MC4R KO and NPY KO mice have increased BMD. However, reduction of alpha-MSH, the primary ligand of MC4R by up to 94% and the lack of detectable NPY in the hypothalamus of CPE KO do not recapitulate the single-gene KO phenotypes. This study highlights the complex physiological interplay between peptides involved in energy metabolism and bone formation and furthermore suggests the possibility that patients, bearing CPE and CART mutations leading to inactive forms of these molecules, may be at a higher risk of developing osteoporosis.

Topics: Absorptiometry, Photon; alpha-MSH; Animals; Biomarkers; Bone Density; Bone Remodeling; Bone Resorption; Calcium; Carboxypeptidase H; Enzyme-Linked Immunosorbent Assay; Female; Hypothalamus; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Osteoclasts; Osteoprotegerin; Peptide Hormones; Pituitary Gland, Intermediate; Protein Array Analysis; RANK Ligand

To investigate the association of single nucleotide polymorphism (SNP) rs4355801 near osteoprotegerin (OPG) gene and rs3736228 in low-density lipoprotein receptor-related protein 5 (LRP5) gene with metabolic phenotypes [body mass index (BMI), waist-hip ratio, glucose, total cholesterol (CHO), and triglyceride], we carried out a population-based association study in Uyghur population living in Xinjiang Uyghur Autonomous Region of China. We observed a significant higher level of BMI in AG/AA carriers than in GG carriers (P = 0.022) for rs4355801. Subjects with the AG/GG genotype significantly increased the risk of BMI related obesity than subjects with the AA genotype, with an odds ratio of 1.31 (95% CI 1.09-1.56, P = 0.005). The association remained significant after controlling for covariates of age and gender. In addition, we observed a significant higher level of CHO in CT/TT carriers than in CC carriers (P = 0.021) for rs3736228. Our observations provide the first evidence that rs4355801 near OPG gene may confer susceptibility to obesity. In addition, SNP rs3736228 in LPR5 gene may affects the level of CHO in Uyghur population.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Body Mass Index; China; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Obesity; Osteoprotegerin; Polymorphism, Single Nucleotide

Osteoprotegerin (OPG) is a soluble tumour necrosis factor-receptor-like molecule present in connective tissues, especially bone and vasculature. It is known to accumulate in the arterial wall in diabetes. As its synthesis in vascular cells is decreased by insulin, we wanted to elucidate the acute effects of insulin on plasma OPG concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls.. The study population consisted of ten type 2 diabetic, ten obese subjects, and ten lean subjects with no family history of diabetes.. All subjects underwent a 4-h euglycemic-hyperinsulinemic clamp. Plasma OPG, insulin, lactate, HbA1c, cholesterol, triglycerides, free fatty acids (FFA), and glucose disposal rate were measured before and at the end of the clamp.. Baseline OPG concentrations did not differ significantly between groups. Insulin infusion decreased plasma OPG concentrations in all groups (P<0.01); however, the fall in OPG was 50% less in obese and type 2 diabetic individuals (P=0.007). Baseline OPG correlated with fasting insulin, baseline lactate, and low density lipoprotein cholesterol in the diabetic group, and with baseline FFA in the lean group. The relative change of OPG in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group.. Acute hyperinsulinemia decreases plasma OPG, but with diminished effect in individuals with type 2 diabetes and obesity. Increased levels of OPG in arteries and plasma in diabetes together with the capability of plasma OPG as a cardiovascular risk predictor may be related to the described effects of insulin.

Topics: Acute Disease; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Osteoprotegerin; Risk Factors

Osteoprotegerin (OPG), an inhibitor of osteoclastic bone resorption, has a variety of functions including anti-inflammatory effects and a possible cardiovascular protective role. Both low-grade chronic inflammation and cardiovascular risk are increased in women with the polycystic ovary syndrome (PCOS). We aimed to study serum OPG concentrations in PCOS patients.. Case-control study including 40 PCOS patients matched with 40 non-hyperandrogenic women for age and body mass index.. Basal serum sampling and standard oral glucose tolerance test, and measurement of serum OPG concentrations by commercial ELISA.. Serum OPG concentrations were lower in women with PCOS compared with those of controls (304+/-120 vs 363+/-105 pg/ml respectively; F=7.641, P=0.007) independently of obesity. No differences were observed in serum receptor activator of nuclear factor-kappaB ligand (RANKL) levels and in the RANKL/OPG molar ratio. A multivariate linear regression model (R(2)=0.208, F=6.579, P=0.001) showed that PCOS (beta=-0.281, P=0.008), obesity (beta=-0.245, P=0.022) and age (beta=0.296, P=0.006) were predictive of serum OPG concentrations.. Serum OPG concentrations are reduced in PCOS patients independently of obesity. Considering the anti-inflammatory effects of OPG, its reduced serum concentrations might contribute to the proinflammatory state and cardiovascular risk of PCOS patients.

Topics: Adult; Blood Pressure; Case-Control Studies; Down-Regulation; Female; Gonadal Steroid Hormones; Hirsutism; Humans; Obesity; Osteoprotegerin; Polycystic Ovary Syndrome; RANK Ligand; Sex Hormone-Binding Globulin; Testosterone

Visceral obesity and aortic calcification are both associated with cardiovascular events. The purpose of this study was to examine if visceral obesity was associated with the severity of abdominal aortic calcification.. One hundred and forty eight patients with peripheral artery disease were assessed by CT angiography. The severity of infrarenal abdominal aortic calcification was measured using a validated technique. The size of the visceral and subcutaneous compartments was estimated from anthropometric measurements made from the same CT. Calcification and anthropometric measurements were compared with Spearman's correlation and multiple logistic regression (adjusting for age, gender, hypertension, diabetes, smoking and cholesterol).. The relative size of the visceral compartment estimated from CT diameter ratios was correlated with abdominal aortic calcification severity, r=0.27, p=0.001 and independently associated with calcification allowing for other cardiovascular risk factors (OR 6.63, 95% CI 1.90-23.14). The relative size of the visceral compartment was associated with serum osteoprotegerin levels, suggesting a possible mechanism underlying the detrimental influence of visceral adiposity.. The association of visceral adiposity and arterial calcification suggests one mechanism, which may contribute to the detrimental effects of central obesity.

Topics: Adipokines; Aged; Angiography; Anthropometry; Aorta, Abdominal; Aortic Diseases; Calcinosis; Cohort Studies; Female; Humans; Intra-Abdominal Fat; Logistic Models; Male; Middle Aged; Obesity; Osteoprotegerin; Risk Factors; Severity of Illness Index; Tomography, X-Ray Computed

We analyzed the relation of osteoprotegerin (OPG) with insulin sensitivity, lipid profile, serum glutamic pyruvic transaminase (SGPT), adipocytokines, and C-reactive protein (CRP) in obese and non-obese subjects.. In the study, 170 subjects (106 obese and 64 non-obese, sex ratio female/male=2.03) were included. Thirty-two obese subjects were reevaluated 6 months after the weight loss induced by bariatric surgery.. OPG did not differ between obese and non-obese subjects (respective mean values 5.17 and 4.96 pmol/l) or according to gender, but was positively correlated with age (P<0.0001 for both groups). OPG was statistically higher in 18 obese diabetic subjects compared with non-diabetics (P=0.03). After adjustment for age, no significant correlation was found between OPG and body mass index (BMI), waist, systolic and diastolic blood pressure, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, leptin, and adiponectin in both the obese and non-obese subjects. However, OPG was positively correlated with homeostasis model assessment (HOMA) index and SGPT levels in obese subjects at baseline (r=0.295, r=0.20, P<0.05) and after adjustment for age (r=0.28, r=0.20, P<0.05). OPG was also significantly correlated with CRP; this correlation persisted after adjustment for age in obese subjects (r=0.30, P<0.01). In a multivariate analysis in the obese group, HOMA index and CRP were independent predictors of OPG while SGPT was not. Six months post-surgery, OPG did not change, despite a significant reduction in glucose, SGPT, cholesterol, triglycerides, CRP, and leptin values (P=0.02, P=0.006, P=0.007, P<0.001, P<0.001, P<0.001 respectively) and a significant increase in adiponectin and HDL values (P<0.001 for both variables).. Our results show that in obese subjects, OPG is not related to BMI. However, we describe new relationships between OPG and both HOMA index and CRP.

Topics: Adipokines; Adult; Alanine Transaminase; Bariatric Surgery; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Osteoprotegerin; Regression Analysis; Risk Factors; Triglycerides; Weight Loss

To assess the influence of weight reduction therapy on serum osteoprotegerin (OPG) concentration in obese patients and compare these results with normal-weight controls.. Forty-three obese women (BMI, 36.7 +/- 4.1 kg/m2; mean age, 50.1 +/- 4.5 years) were studied. The control group consisted of 19 normal-weight women (BMI, 24.2 +/- 2.1 kg/m2; mean age, 53.8 +/- 5.2 years). In all patients, serum concentrations of OPG, C telopeptide of type I collagen containing the cross-linking site (CTX), osteocalcin, parathormone, 25-(OH)-D3 (vitamin D), and total calcium and phosphorus were assessed before and after a 3-month weight reduction therapy.. In obese subjects, serum concentrations of OPG, 25-(OH)-D3, osteocalcin, total calcium, and phosphorus were significantly lower, and serum concentration of parathormone was significantly higher, before weight reduction therapy in comparison with normal-weight controls. After weight reduction, a significantly higher serum concentration of 25-(OH)-D3 and CTX and significantly lower concentration of OPG were found.. Serum concentration of OPG was significantly lower in obese patients in comparison with normal-weight controls. Weight reduction therapy resulted in further decrease in OPG serum concentrations. Therefore, OPG cannot be treated as a protective factor from bone loss in obese patients.

Topics: Body Mass Index; Bone Density; Calcifediol; Calcium; Collagen Type I; Female; Humans; Middle Aged; Obesity; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Peptides; Phosphorus; Weight Loss; X-Rays

We investigated the relationship between circulating leptin and osteoprotegerin (OPG) levels and insulin resistance assessed by HOMA-IR in premenopausal obese and normal weight women. Thirty four obese women (age 31 +/- 8 years) (BMI 35 +/- 4 kg/m(2)) with 19 healthy controls (age 31 +/- 7 years) (BMI <25 kg/m(2)) (BMI 21 +/- 2 kg/m(2)) were included in the study. Women were healthy and had no osteoporosis. Circulating leptin levels were significantly higher in obese women (17.11 +/- 2.05 ng/mL vs. 8.38 +/- 4.71 ng/mL, p <0.0001) and decreased OPG levels were found (14.7 +/- 7.15 pg/mL vs. 19.17 +/- 6.37 pg/mL, p = 0.03). Leptin showed a positive correlation with BMI (r = 0.851, p <0.0001), waist-to-hip ratio (r = 0.692, p <0.0001), fasting insulin (r = 0.441, p <0.001), HOMA-IR (r = 0.412, p = 0.002), fibrinogen (r = 0.387, p = 0.004), uric acid (r = 0.293, p = 0.033), hematocrit (r = 0.394, p = 0.003), systolic (r = 0.504, p <0.0001), and diastolic blood pressure (r = 0.363, p = 0.008). OPG showed a negative correlation with insulin (r = -0.341, p = 0.013) and HOMA-IR (r = -0.324, p = 0.018). In obese women group, the regression equation of HOMA-IR was (HOMA-IR = [0.095 x leptin]-[0.051 x OPG] + 1.71). However, there was no relation between leptin and OPG levels. In conclusion, circulating leptin and OPG levels were related to insulin resistance in premenopausal obese women. However, leptin had no interference in OPG in premenopausal women.

Topics: Adult; Blood Glucose; Body Mass Index; Case-Control Studies; Fasting; Female; Health Status; Humans; Insulin Resistance; Leptin; Obesity; Osteoprotegerin; Premenopause

We investigated the relationship between insulin resistance and serum osteoprotegerin (OPG) levels in healthy obese subjects and healthy lean controls.. Fifty obese subjects (age: 31+/-8 years) and 24 lean controls (age: 30+/-7 years) were included in the study. We used the homeostasis model assessment for insulin resistance (HOMA-IR) index as the index of insulin resistance. OPG levels were measured with the commercial ELISA kit. Obese subjects were studied in three groups: Group I (n = 25) HOMA-IR index < 2.24, Group II (n = 13) index 2.24-3.59, Group III (n = 12) index > 3.59. Group IV (n = 24) was the lean controls with HOMA-IR index < 2.24.. Obese subjects with increased insulin resistance (Group III) had lower OPG values than other groups (11.88+/-7.43 pg/ml, 16.39+/-6.39 pg/ml, 17.37+/-9.61 pg/ml, and 18.1+/-6.65 pg/ml, respectively; Group I versus Group III p = 0.036; Group III versus Group IV p = 0.012). We also found significant inverse correlations between OPGc (corrected for BMI) and fasting glucose (r = -0.325, p = 0.005), fasting insulin (r = -0.404, p = 0.0001) as well as HOMA-IR (r = -0.428, p = 0.0001). Increased fibrinogen level was found in Group III than Group IV (9.32+/-1.97 micromol/l versus 7.47+/-1.65 micromol/l, respectively; p = 0.005). In conclusion, insulin resistance in obesity is associated with decreased serum OPG levels and increased fibrinogen levels. The relationship between serum OPG levels and HOMA-IR may provide an insight into vascular endothelial dysfunction in obesity.

Topics: Adult; Blood Glucose; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Fibrinogen; Glycoproteins; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Obesity; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Receptor activator of nuclear factor KB (RANK) and osteoprotegerin (OPG) represent the ligand and decoy receptor, respectively, of a pleiotropic cytokine system that regulates bone metabolism and vascular biology. Several studies supported systemic microvascular abnormalities in patients with cardiac syndrome X (CSX). This study investigates serum OPG levels in healthy obese subjects and healthy lean controls affected by cardiac syndrome X.. We compared the OPG levels in 8 patients with cardiac syndrome X [2 males, 6 females; age: 46+/-6 yr; body mass index (BMI): 30+/-5 kg/m2] with 24 obese subjects (8 males, 16 females; age: 38+/-5 yr; BMI: 35+/-5 kg/m2) and 15 healthy lean controls (6 males, 9 females; age: 36+/-5 yr; BMI: 23+/-2 kg/m2; BMI<25kg/m2).. Serum OPG levels in patients with cardiac syndrome X were lower than those in obese subjects and lean controls (11.45+/-8.36 pg/ml, 14.78+/-8.22 pg/ml, 19.24+/-6.96 pg/ml, respectively, cardiac syndrome X vs lean controls, p=0.039).. Serum OPG levels are lower in patients with CSX. Further studies on the mechanisms of OPG in microangiopathy may help to evaluate the OPG system role as a marker for disease activity, prognosis and response to therapy in cardiovascular diseases.

Topics: Adult; Case-Control Studies; Female; Glycoproteins; Humans; Male; Microvascular Angina; Middle Aged; Obesity; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor