keratan-sulfate and Obesity

To determine the effects of exercise and weight loss interventions on serum levels of four biomarkers and to examine if changes in biomarker levels correlate with clinical outcome measures in obese and overweight adults with knee osteoarthritis (OA).. Serum was obtained at baseline, 6 and 18 months from 193 participants in Arthritis, Diet and Activity Promotion Trial. This was a single-blind 18-month trial with subjects randomized to four groups: healthy-lifestyle (HL), diet (D), exercise (E) and diet plus exercise (D+E). Serum levels of cartilage oligomeric matrix protein (COMP), hyaluronan (HA), antigenic keratan sulfate (AgKS), and transforming growth factor-beta1 (TGF-beta1) were measured by enzyme linked immunosorbent assay.. At baseline there were no significant differences in biomarker levels between intervention groups. When results for all the intervention groups were combined, the levels of HA were found to be negatively correlated with medial joint space width and positively correlated with Kellgren-Lawrence scores (K-L scores) while TGF-beta1 levels negatively correlated with K-L scores. When biomarker levels measured at 6 and 18 months were adjusted for baseline values, age, gender, and body mass index, weak but significant differences between intervention groups were present for mean levels of COMP and TGF-beta1. Furthermore, AgKS levels averaged over all groups tended to decrease over time. There were no significant associations of baseline biomarkers and the follow-up outcomes. Weak associations were noted between change in the biomarkers at 18 months and change in outcome measures that included change in weight with AgKS and COMP and change in Western Ontario and McMaster Universities Osteoarthritis Index pain with AgKS.. Overall, the E and D interventions did not show a consistent effect on levels of potential OA biomarkers. The four biomarkers showed differences in correlations with outcome measures suggesting that they may measure different aspects of disease activity in OA. The strongest correlations were between serum HA and radiographic measures of OA at baseline.

Topics: Aged; Biomarkers; Body Mass Index; Cartilage Oligomeric Matrix Protein; Diet, Reducing; Enzyme-Linked Immunosorbent Assay; Exercise Therapy; Extracellular Matrix Proteins; Female; Glycoproteins; Humans; Hyaluronic Acid; Keratan Sulfate; Life Style; Male; Matrilin Proteins; Obesity; Osteoarthritis, Knee; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Time Factors; Weight-Bearing

The purposes of this pilot study were to determine if a combined dietary and exercise intervention would result in significant weight loss in older obese adults with knee osteoarthritis, and to compare the effects of exercise plus dietary therapy with exercise alone on gait, strength, knee pain, biomarkers of cartilage degradation, and physical function.. Single-blind, two-arm, randomized clinical trial conducted for 24 weeks.. A university health and exercise science center.. Twenty-four community-dwelling obese older adults aged > or = 60 years, body mass index > or = 28, knee pain, radiographic evidence of knee osteoarthritis, and self-reported physical disability.. Randomization into two groups: exercise and diet (E&D) and exercise alone (E). Exercise consisted of a combined weight training and walking program for 1 hour three times per week. The dietary intervention included weekly sessions with a nutritionist utilizing cognitive-behavior modification to change dietary habits to reach a group goal of an average weight loss of 15 lb (6.8 kg) over 6 months.. All measurements were conducted at baseline and 3 and 6 months, except for synovial fluid analysis, which was obtained only at baseline and 6 months. In addition, weight was measured weekly in the E&D group. Physical disability and knee pain were measured by self-report and physical performance was measured using the 6-minute walk and stair climb tasks. Biomechanical testing included kinetic and kinematic analysis of gait and isokinetic strength testing. Synovial fluid was analyzed for levels of total proteoglycan, keratan sulfate, and interleukin-1 beta.. Twenty-one of the 24 participants completed the study, with one dropout in the E&D group and two in the E group. The E&D group lost a mean of 18.8 lb (8.5 kg) at 6 months compared with 4.0 lb (1.8 kg) in the E group (P = .01). Significant improvements were noted in both groups in self-reported disability and knee pain intensity and frequency as well as in physical performance measures. However, no statistical differences were found between the two groups at 6 months in knee pain scores or self-reported performance measures of physical function. There was no difference in knee strength between the groups, with both groups showing modest improvements from baseline to 6 months. At 6 months, the E&D group had a significantly greater loading rate (P = .03) and maximum braking force (P = .01) during gait. There were no significant between-group differences in the other biomechanical measures. Synovial fluid samples were obtainable at both baseline and 6 months in eight participants (four per group). The level of keratan sulfate decreased similarly in both groups from an average baseline of 96.8 +/- 37.1 to 71.5 +/- 23 ng/microg total proteoglycan. The level of IL-1 decreased from 25.3 +/- 9.8 at baseline to 8.3 +/- 6.1 pg/mL. The decrease in IL-1 correlated with the change in pain frequency (r = -0.77, P = .043).. Weight loss can be achieved and sustained over a 6-month period in a cohort of older obese persons with osteoarthritis of the knee through a dietary and exercise intervention. Both exercise and combined weight loss and exercise regimens lead to improvements in pain, disability, and performance. Moreover, the trends in the biomechanical data suggest that exercise combined with diet may have an additional benefit in improved gait compared with exercise alone. A larger study is indicated to determine if weight loss provides additional benefits to exercise alone in this patient population.

Topics: Activities of Daily Living; Aged; Biomechanical Phenomena; Body Mass Index; Combined Modality Therapy; Diet, Reducing; Exercise Therapy; Female; Gait; Humans; Interleukin-1; Keratan Sulfate; Male; Obesity; Osteoarthritis, Knee; Pain; Pilot Projects; Proteoglycans; Single-Blind Method; Synovial Fluid; Walking; Weight Lifting; Weight Loss

We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte-specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome-scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809, enables mechanistic insights into adipocyte metabolism on a genome-wide level, and can serve as a scaffold for integration of omics data to understand the genotype-phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling.

Topics: Adipocytes; Androsterone; Body Mass Index; G(M2) Ganglioside; Genome, Human; Heparitin Sulfate; Humans; Immunohistochemistry; Keratan Sulfate; Mitochondria; Models, Biological; Obesity; Proteome; Reproducibility of Results; Transcriptome

The basis of hepatocellular injury and progressive fibrosis in a subset of patients with nonalcoholic fatty liver disease (NAFLD) is poorly understood. We sought to identify hepatic proteins that are differentially abundant across the histologic spectrum of NAFLD. Hepatic protein abundance was measured in liver samples from four groups (n = 10 each) of obese (body mass index >30 kg/m(2)) patients: (1) obese normal group (normal liver histology), (2) simple steatosis (SS), (3) nonalcoholic steatohepatitis (NASH)-mild (steatohepatitis with fibrosis stage 0-1), and (4) NASH-progressive (steatohepatitis with fibrosis stage 2-4). Hepatic peptides were analyzed on an API Qstar XL quadrupole time-of-flight mass spectrometer using Analyst QS software. Linear trends tests were performed and used to screen for differential abundance. Nine known proteins were expressed with differential abundance between study groups. For seven proteins differential abundance is likely to have been on the basis increased hepatic lipid content and/or inflammation. Lumican, a 40-kDa keratin sulfate proteoglycan that regulates collagen fibril assembly and activates transforming growth factor-beta and smooth muscle actin, was expressed similarly in obese normal and SS but was overexpressed in a progressive manner in NASH-mild versus SS (124%, P < 0.001), NASH-progressive versus NASH-mild (156%, P < 0.001) and NASH-progressive versus obese normal (178%, P < 0.001). Fatty acid binding protein-1 (FABP-1), which is protective against the detergent effects of excess free fatty acids, facilitates intracellular free fatty acid transport and is an important ligand for peroxisome proliferator-activated receptor-mediated transcription, was overexpressed in SS when compared to the obese normal group (128%, P < 0.001), but was paradoxically underexpressed in NASH-mild versus SS (73%, P < 0.001), NASH-progressive versus NASH-mild (81%, P < 0.001), and NASH-progressive versus obese normal (59%, P < 0.001).. Histologically progressive NAFLD is associated with overexpression of lumican, an important mediator of fibrosis in nonhepatic tissues, whereas FABP-1 is paradoxically underexpressed in NASH, suggesting a new potential mechanism of lipotoxicity in NAFLD. Further studies are needed to determine the biologic basis of lumican and/or FABP-1 dysregulation in NAFLD.

Topics: Adult; Chondroitin Sulfate Proteoglycans; Fatty Acid-Binding Proteins; Fatty Liver; Female; Humans; Immunohistochemistry; Keratan Sulfate; Liver; Lumican; Male; Middle Aged; Obesity; Polymerase Chain Reaction; Proteomics; RNA, Messenger; Tandem Mass Spectrometry