Gareth Denyer

Obesity and Risk of Low Self-esteem: A Statewide Survey of Australian Children.

OBJECTIVE. There is variation in the psychological distress associated with child obesity. Low self-esteem, when observed, provides very little information about the nature of the distress and no indication of the proportion of obese children affected. This study used a domain approach to self-competence to evaluate self-esteem in a representative sample of Australian children. PARTICIPANTS AND METHODS. A total of 2813 children (mean age: 11.3 years) took part in the study. They were recruited from 55 schools and were all in the last 2 years of primary school. Participants completed the Self-perception Profile for Children, a measure of body shape perception, and their height and weight were measured. RESULTS. Obese children had significantly lower perceived athletic competence, physical appearance, and global self-worth than their normal weight peers. Obese girls scored lower in these domains than obese boys and also had reduced perceived social acceptance. Obese children were 2–4 times more likely than their normal weight peers to have low domain competence. In terms of prevalence, 1 of 3 obese boys and 2 of 3 obese girls had low appearance competence, and 10% and 20%, respectively, had low global self-worth. Body dissatisfaction mediated most of the association between BMI and low competence in boys but not in girls. CONCLUSIONS. Obesity impacts the self-perception of children entering adolescence, especially in girls, but in selected areas of competence. Obese children are at particular risk of low perceived competence in sports, physical appearance, and peer engagement. Not all obese children are affected, although the reasons for their resilience are unclear. Quantifying risk of psychological distress alongside biomedical risk should help in arguing for more resources in child obesity treatment.

Glycemic index, postprandial glycemia, and the shape of the curve in healthy subjects: analysis of a database of more than 1000 foods

BACKGROUND The glycemic index (GI) characterizes foods by using the incremental area under the glycemic response curve relative to a similar amount of oral glucose. Its ability to differentiate between curves of different shapes, the peak response, and other aspects of the glycemic response is debatable. OBJECTIVE The objective was to explore the association between a foods GI and the shape of the curve in healthy individuals. DESIGN A large database of 1,126 foods tested by standardized GI methodology in 8-12 healthy subjects was analyzed systematically. Each foods absolute and incremental blood glucose concentrations were compared at individual time points with the GI. The average curve was generated for low-GI (< or = 55), medium-GI (56-69), and high-GI (> or = 70) foods within major food categories. RESULTS The GI of individual foods was found to correlate strongly with the incremental and actual peak (Spearmans correlations of r = 0.76 and r = 0.73, respectively), incremental and actual glucose concentration at 60 min (r = 0.70 and r = 0.66, respectively), and maximum amplitude of glucose excursion (r = 0.68) (all P < 0.001). In contrast, there was only a weak correlation between the foods GI and the 120-min glucose concentration (incremental r = 0.20, P < 0.001; absolute r = 0.16, P < 0.001). Within food groups, the mean GI, 30- and 60-min glucose concentrations, and maximum amplitude of glucose excursion varied significantly for foods classified as having a low, medium, or high GI (P < 0.001). CONCLUSIONS The GI provides a good summary of postprandial glycemia. It predicts the peak (or near peak) response, the maximum glucose fluctuation, and other attributes of the response curve.

Targeted Disruption of the Basic Kruppel-Like Factor Gene (Klf3) Reveals a Role in Adipogenesis†

ABSTRACT Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebpα promoter. We find that C/ebpα is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebpα promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.

The postprandial response of adiponectin to a high-fat meal in normal and insulin-resistant subjects

OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal.DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal.SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20).MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting.RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting.CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.

Genome-wide analysis of gene expression in T cells to identify targets of the NF-kappa B transcription factor c-Rel

It is well established that the NF-κB family of transcription factors serves a major role in controlling gene expression in response to T cell activation, but the genome-wide roles of individual family members remain to be determined. c-Rel, a member of the NF-κB family, appears to play a specific role in T cell function because T cells from c-Rel−/− animals are defective in their response to immune signals. We have used expression profiling to identify sets of genes that are affected by either deletion or overexpression of c-Rel in T cells. Very few of these genes exhibit a strong requirement for c-Rel; rather, c-Rel appears to modulate the expression of a large number of genes in these cells. The sets of c-Rel-affected genes are significantly enriched for genes containing consensus NF-κB/Rel sites in their proximal promoter regions. In addition, their promoters contain a higher average density of NF-κB/Rel sites compared with all genes represented on the microarrays. A transcriptional module comprised of two closely spaced c-Rel consensus sites is found with higher frequency in the c-Rel-affected gene sets and may represent an important control module for genes regulated by c-Rel or other NF-κB family members. We confirmed the importance of these findings on a subgroup of genes by using quantitative PCR to monitor gene expression as well as in vitro c-Rel/DNA binding assays and luciferase reporter assays. The c-Rel-regulated genes identified here support a role for c-Rel in inflammatory responses as well as in the promotion of cell growth and survival.

Role of the Gut in Visceral Fat Inflammation and Metabolic Disorders

IntroductIon Obesity and diabetes are rapidly increasing in both developed and developing countries with enormous personal and economic cost implications. Type 2 diabetes was recognized over 20 years ago, in the seminal Banting Lecture of Reaven (1), as part of a cluster of metabolic disorders including obesity (defined by BMI (weight (kg)/height (m)2)), hypertension and dyslipidemia (high triglycerides and low high-density lipoprotein-cholesterol) and with cardiovascular disease as an endpoint (in both senses of the word). Since then, both central adiposity and circulating inflammatory markers (such as C-reactive protein) are understood to also be critical predictors in the metabolic syndrome. Key questions of major importance are: (i) Why is visceral fat particularly deleterious; (ii) What generates the chronic low-grade inflammatory profile of obesity; and (iii) Are these linked to a common etiology of metabolic dysregulation.

Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker

Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Downs syndrome (DS), affecting up to 10% of DS neonates. In 20–30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2–4 years of age. The TMD and AMKL blasts are morphologically and immuno‐phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG‐U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0·05) by Students t‐test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence‐activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1‐mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma‐derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL‐M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self‐regressive from the progressive phenotype.

The molecular signature of CD8+ T cells undergoing deletional tolerance

Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T-cell anergy or deletion. Although the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T-cell deletion. Here, we determined the gene expression signature of peripheral CD8(+) T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the proapoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T-cell deletion. Bim up-regulation was paralleled by defective interleukin-7 receptor alpha (IL-7Ralpha) chain reexpression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy, suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised.

Evaluation of general nutrition knowledge in elite Australian athletes

The aim of the present study was to investigate and benchmark the level of general nutrition knowledge in elite Australian athletes (EA) against a similar aged community (CM) and criterion sample with dietetic training (DT). EA (n 175), CM (n 116) and DT (n 53) completed the General Nutrition Knowledge Questionnaire (GNKQ), which assesses four domains (sections A-D) of general nutrition knowledge (section A: dietary guidelines; section B: sources of nutrients; section C: choosing everyday foods; section D: diet-disease relationships). Age, sex and education level were collected in all groups, and athletic calibre and sport type (team or individual) in EA. Dietitians and nutrition scientists (n 53) re-examined the GNKQ for content validity, resulting in instrument revision (R-GNKQ; ninety-six items). Psychometric assessment (internal consistency: Cronbach-α; test-retest: Spearman rank correlation) was performed in a sub-sample (n 28). Independent t tests, ANOVA and ANCOVA (χ² for categorical variables) were used to assess between-group differences. DT scored higher than EA and CM in all sub-sections and overall (P < 0·005). EA scored lower than CM in GNKQ for section B (P < 0·005) and overall (P < 0·005), and in R-GNKQ for section B (P < 0·005), section C (P < 0·005), section D (P = 0·006) and overall (P < 0·005). Overall score was influenced by age (P = 0·036 for GNKQ: P = 0·053 for R-GNKQ), sex (P = 0·016 for GNKQ: P = 0·003 for R-GNKQ) and athletic calibre (P = 0·029 for R-GNKQ only), but not level of education, living situation or ethnicity. EA and CM performed best on section A and worst on D. EA had lower overall general knowledge scores than CM. This was significantly influenced by age and sex.

Endothelial cells preparing to die by apoptosis initiate a program of transcriptome and glycome regulation

The protein‐based changes that underlie the cell biology of apoptosis have been extensively studied. In contrast, mRNA‐ and polysaccharide‐based changes have received relatively little attention. We have combined transcriptome and glycome analyses to show that apoptotic endothelial cell cultures undergo programmed changes to RNA transcript abundance and cell surface polysaccharide profiles. Although a few of the transcriptome changes were protective, most appeared to prepare cells for apoptosis by decreasing the reception and transduction of pro‐ survival signals, increasing pro‐death signals, increasing abundance of apoptotic machinery, inhibiting cellular proliferation, recruiting phagocytes to regions of cell death, and promoting phagocytosis. Additional transcriptomal changes appeared to alter the synthesis and modification of cell surface glycosaminoglycans. The resultant reduced abundance of sulphated cell surface glycosaminoglycans may further promote cell death by inhibiting the presentation of extracellular matrix‐tethered survival factors to their receptors on dying cells. We propose that the transcriptome and glycome regulation presented here synergize with previously described protein‐based changes to guide the apoptotic program.