Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

Bone mineral density after childhood cancer in 346 long-term adult survivors of childhood cancer.

SUMMARY: More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids. INTRODUCTION: Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer. METHODS: This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1. RESULTS: Survivors had a lower BMDTB and BMDLS (mean SDS -0.55; p<0.001 and -0.30; p<0.001, respectively) as compared to healthy peers. Osteopenia (BMDTB and/or BMDLS) was present in 45% of the survivors. Multivariate logistic regression analyses identified age at diagnosis<12 years, age>30 years at follow-up, male gender, underweight at follow-up and treatment with cranial-spinal radiotherapy or prednisone as independent prognostic factors for osteopenia. CONCLUSIONS: This large cohort of childhood cancer survivors identified osteopenia in 45% of CCS. This indicates that greater awareness is warranted, especially in survivors who are older than 30 years, male, have underweight and were treated with cranial-spinal radiotherapy and/or steroids.

Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia.

Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 µmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

Does dexamethasone induce more neuropsychological side effects than prednisone in pediatric acute lymphoblastic leukemia? A systematic review.

Steroid-induced neuropsychological side effects impact quality of life in children with acute lymphoblastic leukemia. Dexamethasone induces more metabolic side effects than prednisone. To evaluate whether dexamethasone also leads to more neuropsychological side effects, we reviewed all available literature. Randomized controlled trials with neuropsychological function as the primary or secondary outcome did not show clinically meaningful differences between dexamethasone and prednisone on cognition, mood or behavior.

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals.

AIMS/HYPOTHESIS: Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies. METHODS: We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR. RESULTS: We observed significant associations of BMI-increasing alleles at five BMI loci with lower levels of 2 h glucose (RBJ [also known as DNAJC27], QPTCL: effect sizes -0.068 and -0.107 SD, respectively), HDL-cholesterol (SLC39A8: -0.065 SD, MTCH2: -0.039 SD), and diastolic BP (SLC39A8: -0.069 SD), and higher and lower levels of LDL- and total cholesterol (QPTCL: 0.041 and 0.042 SDs, respectively, FLJ35779 [also known as POC5]: -0.042 and -0.041 SDs, respectively) (all p < 2.4 × 10(-4)), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (GRB14: 0.069 SD) and lower fasting glucose levels (CPEB4: -0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (-0.005 SD), diastolic BP (-0.006 SD) and 2 h glucose (-0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol (-0.015 SD) and higher triacylglycerol levels (0.014 SD) (all p < 2.9 × 10(-3)), independent of BMI and/or WHR. CONCLUSIONS/INTERPRETATION: These pleiotropic effects of obesity-susceptibility loci provide novel insights into mechanisms that link obesity with metabolic abnormalities.

Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples.

BACKGROUND: Meta-analysis of case-control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes. OBJECTIVE: We aimed to validate association of these variants with obesity-related traits in population-based samples. DESIGN: Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r (2)>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age(2) in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods. RESULTS: We had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (ß=0.013 s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3). CONCLUSION: Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.

Body composition in 10-13-year-old children: a comparison between air displacement plethysmography and deuterium dilution.

OBJECTIVE: Air diplacement plethysmography (ADP) has become increasingly popular to assess body composition in children. The aim of this study was to compare ADP with deuterium dilution and to investigate the effect of using child-specific prediction equations to correct raw body volume from ADP for thoracic gas volume (TGV) and body surface area (BSA). METHODS: Thirty-seven healthy Dutch children (17 girls, 20 boys) aged 10-13 years were recruited. Body volume was measured using the Bod Pod. Both adult and child-specific prediction equations were used to correct raw body volume from the Bod Pod for TGV and BSA. Total body water (TBW) was assessed using deuterium dilution. Child-specific densities and hydration fractions of fat-free mass were used to convert body volume and TBW to percentage fat mass (%FM). Correlation and agreement between methods was assessed using linear regression analysis and Bland-Altman plots. RESULTS: Despite a high correlation between the Bod Pod and deuterium dilution (R=0.91, p <0.001), a significant difference was found between %FM obtained using the Bod Pod and deuterium dilution (p <0.001), regardless of the equation used to correct raw body volume for TGV and BSA. Bland-Altman plots showed a systematic bias towards a smaller difference between techniques at higher %FM. CONCLUSION: Significant differences in %FM were found between both methods. Given the underlying assumptions to translate body volume or TBW to %FM, it is recommended to use a 3- or 4-compartment model when assessing body composition in children.

Skeletal muscle fiber-type distribution and habitual physical activity in daily life.

The capacity to perform physical activity largely depends on physical fitness. Muscle fiber-type distribution (Muscle(FTD)) is associated with physical fitness and may influence the capacity to perform physical activity. The purpose of this study was to determine whether habitual physical activity in daily life (PA(DL)) and Muscle(FTD) are related. Thirty-eight healthy non-athletes (31 women, 7 men) were recruited. PA(DL) was measured twice for 14 days using a tri-axial accelerometer for movement registration (Tracmor). From Tracmor output, the proportion of time subjects were physically active at low, moderate, and high intensities was determined (%Low, %Moderate, and %High, respectively). A total activity index (PA(index)) and sub-scores on work, leisure-time and sports were obtained using the Baecke questionnaire. Muscle(FTD) was determined using immuno-fluorescence against respective myosin heavy chain isoforms. No relationship was observed between PA(DL) and Muscle(FTD). %Low, %Moderate, and %High, as well as PA(index) and its sub-scores, were not related to Muscle(FTD) either. The time spent on sports was associated with the proportion of type I and II(X) fibers (P=0.06 and P<0.01, respectively). In conclusion, Muscle(FTD) probably cannot explain why some people are more prone to engaging in physical activities than others.

SNP analyses of postprandial responses in (an)orexigenic hormones and feelings of hunger reveal long-term physiological adaptations to facilitate homeostasis.

BACKGROUND: The postprandial responses in (an)orexigenic hormones and feelings of hunger are characterized by large inter-individual differences. Food intake regulation was shown earlier to be partly under genetic control. OBJECTIVE: This study aimed to determine whether the postprandial responses in (an)orexigenic hormones and parameters of food intake regulation are associated with single nucleotide polymorphisms (SNPs) in genes encoding for satiety hormones and their receptors. DESIGN: Peptide YY (PYY), glucagon-like peptide 1 and ghrelin levels, as well as feelings of hunger and satiety, were determined pre- and postprandially in 62 women and 41 men (age 31+/-14 years; body mass index 25.0+/-3.1 kg/m(2)). Dietary restraint, disinhibition and perceived hunger were determined using the three-factor eating questionnaire. SNPs were determined in the GHRL, GHSR, LEP, LEPR, PYY, NPY, NPY2R and CART genes. RESULTS: The postprandial response in plasma ghrelin levels was associated with SNPs in PYY (215G>C, P<0.01) and LEPR (326A>G and 688A>G, P<0.01), and in plasma PYY levels with SNPs in GHRL (-501A>C, P<0.05) and GHSR (477G>A, P<0.05). The postprandial response in feelings of hunger was characterized by an SNP-SNP interaction involving SNPs in LEPR and NPY2R (668A>G and 585T>C, P<0.05). Dietary restraint and disinhibition were associated with an SNP in GHSR (477G>A, P<0.05), and perceived hunger with SNPs in GHSR and NPY (477G>A and 204T>C, P<0.05). CONCLUSIONS: Part of the inter-individual variability in postprandial responses in (an)orexigenic hormones can be explained by genetic variation. These postprandial responses represent either long-term physiological adaptations to facilitate homeostasis or reinforce direct genetic effects.

Body composition is associated with physical activity in daily life as measured using a triaxial accelerometer in both men and women.

BACKGROUND: Activity-related energy expenditure is the most variable component of total energy expenditure and thus an important determinant of energy balance. OBJECTIVE: To determine whether body composition is related to physical activity in both men and women. DESIGN: A total of 134 healthy participants were recruited (80 women, 54 men; aged 21+/-2 years; body mass index, 22.0+/-2.4). Physical activity was measured for a period of 2 weeks using a triaxial accelerometer for movement registration (Tracmor). Percentage body fat (%BF) was determined by underwater weighing and deuterium dilution according to Siri's three-compartment model. RESULTS: The participant characteristics-body mass, height and gender together explained a substantial part of the variation in %BF (R(2)=0.75, SEE=4.0%). Adding physical activity to the model increased the explained variation in %BF with 4% (R(2)=0.79, SEE=3.7%, P<0.001). Taking seasonality into account by adding the number of daylight hours as an independent variable further increased the explained variation with 1% (R(2)=0.80, SEE=3.7%, P<0.05). In analogy, the association was evaluated for both genders separately. In women, %BF and physical activity were significantly associated (P<0.001). In men, %BF was only associated with physical activity when seasonality was taken into account as well (P<0.05). This probably resulted from men participating more in season bound sports, because an association was found without adjusting for seasonality when only men with a consistent year-round participation in sports were considered. CONCLUSION: Evidence was found for an association between body composition and physical activity in both genders. A consistent year-round degree of physical activity appears to be a prerequisite to reveal the association. Moreover, Tracmor-assessed physical activity improves the estimate of %BF when a participant's characteristics are taken into account.