Inhibition of cytokine secretion from adipocytes by 1,25-dihydroxyvitamin D3 via the NF-κB pathway.

Adipose tissue inflammation is an important pathological process in obese people, associated with diabetes and cardiovascular disease. We hypothesized that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits cytokine secretion from adipocytes via direct inhibition of transcription factor nuclear factor-κB (NF-κB). We utilized two different human models. Bone marrow-derived human mesenchymal stromal cells (hMSCs) differentiated into adipocytes, and adipocytes isolated from biopsies stimulated with lipopolysaccharide (LPS) were treated with or without 1,25(OH)(2)D(3). Expression and secretion of interleukin-6 (IL-6) were measured by quantitative RT-PCR analysis and ELISA. Assessment of NF-κB nuclear translocation, DNA binding activity was performed by immunofluorescence (IF) and electrophoretic mobility assay (EMSA). Inhibitor κB (IκB) and its phosphorylation were detected by Western blot (WB) analysis. Simultaneous 1,25(OH)(2)D(3) cotreatment significantly reduced LPS-stimulated (10 ng/ml) IL-6 secretion dose dependently by 15% at 10(-10) M and 26% at 10(-7) M (P<0.05) in hMSCs, while preincubation with 1,25(OH)(2)D(3) (10(-7) M) for 24 h reduced IL-6 secretion by 24 and 35% (P<0.001) and mRNA levels by 34 and 30% (P<0.05) in hMSCs and isolated adipocytes, respectively. 1,25(OH)(2)D(3) suppressed LPS-stimulated IκB phosphorylation-mediated NF-κB translocation into the nucleus were evident from WB, IF, and EMSA. 1,25(OH)(2)D(3) inhibits LPS-stimulated IL-6 secretion in two human adipocyte models via interference with NF-κB signaling.

Prediction of childhood obesity by infancy weight gain: an individual-level meta-analysis.

To assess the predictive ability of infant weight gain on subsequent obesity we performed a meta-analysis of individual-level data on 47,661 participants from 10 cohort studies from the UK, France, Finland, Sweden, the US and Seychelles. For each individual, weight SD scores at birth and age 1 year were calculated using the same external reference (British 1990). Childhood obesity was defined by International Obesity Task Force criteria. Each +1 unit increase in weight SD scores between 0 and 1 year conferred a twofold higher risk of childhood obesity (odds ratio = 1.97 [95% confidence interval (CI) 1.83, 2.12]), and a 23% higher risk of adult obesity (odds ratio = 1.23 [1.16, 1.30]), adjusted for sex, age and birthweight. There was little heterogeneity between studies. A risk score for childhood obesity comprising weight gain 0-1 year, mother's body mass index, birthweight and sex was generated in a random 50% selection of individuals from general population cohorts with available information (n = 8236); this score showed moderate predictive ability in the remaining 50% sample (area under receiving operating curve = 77% [95% CI 74, 80%]). A separate risk score for childhood overweight showed similar predictive ability (area under receiving operating curve = 76% [73, 79%]). In conclusion, infant weight gain showed a consistent positive association with subsequent obesity. A risk score combining birthweight and infant weight gain (or simply infant weight), together with mother's body mass index and sex may allow early stratification of infants at risk of childhood obesity.

Does in utero exposure to synthetic glucocorticoids influence birthweight, head circumference and birth length? A systematic review of current evidence in humans.

Synthetic glucocorticoids are the mainstay treatment for stimulating lung maturation in threatened preterm delivery. Animal studies suggest that in utero exposure to glucocorticoids leads to a reduction in birth size. Smaller birthweight has been associated with higher risk of many chronic diseases. Therefore, the authors undertook a systematic review of human studies examining the association between synthetic glucocorticoid treatment and birth size. Medline, EMBASE, PubMed, Cochrane, Google scholar and Institute of Life Science databases were searched for studies published between 1978 and 2009 investigating the association between synthetic glucocorticoids and birthweight, head circumference, birth length and ponderal index. All studies controlling for gestational age were examined. Seventeen studies were included in the analysis. Nine out of 17 studies reported a reduction in birthweight (range 12-332 g), five of nine a reduction of head circumference (range 0.31-1.02 cm) and two of four a reduction of 0.8 cm in birth length. Despite methodological inconsistencies and limitations that impede clear conclusions, the evidence suggests an association between in utero exposure to synthetic glucocorticoids and reduced birth size.

Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study.

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.

Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoid receptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory. We tested SNP variants at the CNR1 gene in two independent samples-an unselected adolescent sample from Northern Finland, and a family-based sample of trios (an ADHD child and their parents). In addition to using the trios for association study, the parents (with and without ADHD) were used as an additional case/control sample of adults for association tests. ADHD and its co-morbid psychiatric disorders were examined. A significant association was detected for a SNP haplotype (C-G) with ADHD (P = 0.008). A sex by genotype interaction was observed as well with this haplotype posing a greater risk in males than females. An association of an alternative SNP haplotype in this gene was found for post-traumatic stress disorder (PTSD) (P = 0.04 for C-A, and P = 0.01 for C-G). These observations require replication, however, they suggest that the CNR1 gene may be a risk factor for ADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

Relationship between eating behavior, breakfast consumption, and obesity among Finnish and Greek adolescents.

OBJECTIVE: To investigate the relationship between eating-related behaviors, particularly breakfast consumption, and weight status in Finnish and Greek adolescents. METHODS: A total of 6,468 16-year-old Finnish adolescents and 2,842 17- and 18-year-old Greek adolescents, based on the latest follow-up of 2 population-based cohorts, were studied. Univariate analysis examined the associations between breakfast consumption, family meals, emotional eating, bingeing, and weight status in both populations. Multiple logistic regression models focused on the relationship between breakfast consumption and overweight/obesity taking potential confounders into account. RESULTS: Daily breakfast consumption was associated with lower levels of overweight/obesity among Finnish and Greek boys, but not among girls. Adjusting for confounders did not change the result among Greek boys, but adjustment for father's body mass index, weight control, and fear of getting fat attenuated the association among Finnish boys. CONCLUSIONS AND IMPLICATIONS: This study highlights the importance of breakfast consumption, particularly among male adolescents, in obesity prevention programs.

Birth size, infant weight gain, and motor development influence adult physical performance.

PURPOSE: Adult physical performance is recognized as a marker of both current physical capacity and future health. The aim of the study was to examine the independent influences of birth weight, infant weight gain, and infant motor development on a variety of adult physical performance outcomes, in terms of muscular strength, muscular endurance, and aerobic fitness. METHODS: The study population consisted of 4304 individuals from the Northern Finland Birth Cohort 1966 (NFBC 1966) with anthropometry measured at birth and at 1 yr. Infant motor development at age 1 yr was assessed by parentally reported age at first walking supported and standing unaided. At follow-up, aged 31 yr, muscle strength was measured using a handgrip dynamometer, muscle endurance was measured using a timed trunk extension test, and aerobic fitness was estimated from heart rate immediately after a standardized step test. RESULTS: Birth weight was positively associated with muscle strength and aerobic fitness at age 31 yr, and these associations were independent of adult body size (P < 0.001). Greater infant weight gain between 0 and 1 yr was associated with lower muscle endurance (P = 0.004) and poorer aerobic fitness (P = 0.002); these associations seemed to be mediated by adult body size. Independent of infant birth weight and adult body size (height and weight), earlier infant motor development was associated with greater adult muscle strength (P < or = 0.001), muscle endurance (P < 0.001), and aerobic fitness (P < 0.001). CONCLUSIONS: Higher birth weight, lower infant weight gain, and earlier infant motor development independently predict higher levels of adult physical performance for muscle strength, muscle endurance, and aerobic fitness at age 31 yr.