Matthew A. Sabin

Treatment of childhood obesity by retraining eating behaviour: randomised controlled trial

Objective To determine whether modifying eating behaviour with use of a feedback device facilitates weight loss in obese adolescents. Design Randomised controlled trial with 12 month intervention. Setting Hospital based obesity clinic. Participants 106 newly referred obese young people aged 9-17. Interventions A computerised device, Mandometer, providing real time feedback to participants during meals to slow down speed of eating and reduce total intake; standard lifestyle modification therapy. Main outcome measures Change in body mass index (BMI) standard deviation score (SDS) over 12 months with assessment 18 months after the start of the intervention. Secondary outcomes were body fat SDS, metabolic status, quality of life evaluation, change in portion size, and eating speed. Results Using the last available data on all participants (n=106), those in the Mandometer group had significantly lower mean BMI SDS at 12 months compared with standard care (baseline adjusted mean difference 0.24, 95% confidence interval 0.11 to 0.36). Similar results were obtained when analyses included only the 91 who attended per protocol (baseline adjusted mean difference 0.27, 0.14 to 0.41; P<0.001), with the difference maintained at 18 months (0.27, 0.11 to 0.43; P=0.001) (n=87). The mean meal size in the Mandometer group fell by 45 g (7 to 84 g). Mean body fat SDS adjusted for baseline levels was significantly lower at 12 months (0.24, 0.10 to 0.39; P=0.001). Those in the Mandometer group also had greater improvement in concentration of high density lipoprotein cholesterol (P=0.043). Conclusions Retraining eating behaviour with a feedback device is a useful adjunct to standard lifestyle modification in treating obesity among adolescents. Trial registration ClinicalTrials.gov NCT00407420.

Physical activity patterns in nonobese and obese children assessed using minute-by-minute accelerometry.

OBJECTIVE:To determine the levels and patterns of physical activity in a sample of obese (≥99th percentile body mass index (BMI)) and nonobese (<99th percentile BMI) children.DESIGN:Cross-sectional study.SETTING:Children were recruited from schools in Bristol and from the childhood obesity clinic, Bristol Royal Hospital for Children. Children were instructed in the use of the accelerometer either while at school or in the clinic, and wore the instrument while carrying out their normal daily activities for 7 days.PARTICIPANTS:A total of133 children (mean age 10.5±0.8 y). In all 11 (16.9%) of the 65 girls and 14 (20.6%) of the 68 boys were classified as obese (above the 99th percentile for BMI and corresponding to projected adult BMI of 30).MAIN OUTCOME MEASURES:Objectively measured physical activity volume, intensity and pattern.RESULTS:Obese children were significantly less physically active overall than their nonobese counterparts (31 844±13 200 vs 41 844±10 430 counts/h; 95% confidence interval 4407 to 15592; P=0.001). Similarly the obese children spent less time in physical activity of moderate or greater intensity than the nonobese children (9.9±3.9 vs 12.9±4.2 min/h; 95% confidence interval 1.15 to 4.80; P=0.002). Hourly patterns of activity indicated a tendency in obese children to be less active than nonobese children at times when activity was more likely to be determined by free choice, particularly outside of school time.CONCLUSIONS:Obese children demonstrated patterns of physical activity that may have contributed to and are likely to sustain their obesity. Minute-by-minute accelerometry is a valuable tool to investigate physical activity patterns in obese children. It can identify periods when intervention to increase activity may be most appropriate and provide an evidence base for specific exercise prescription in primary and secondary care.SPONSORSHIP:Health Education Authority, NHS R& D South–West

Age-specific stabilization in obesity prevalence in German children: A cross-sectional study from 1999 to 2008

OBJECTIVE Trends of overweight (ov)/obesity (ob) prevalence among German children aged 4-16 years were studied between 1999 and 2008. SUBJECTS Body mass index (BMI) data (>P90 [ov] and >P97 [ob]) from the national CrescNet database were analysed in three age groups: 4-7.99, 8-11.99, and 12-16 years. RESULTS Trend analyses. Data from 272 826 children were analyzed. a) Whole study population aged 4-16 years old. A significant upward trend for ov/ob prevalence was found between 1999 and 2003, and a significant downward trend between 2004 and 2008. b) Subgroup analyses. Ov/Ob prevalence increased in most subgroups studied until 2004. Between 2004 and 2008, a downward trend for ov/ob prevalence was found in children, aged 4-7.99 years, whereas it stabilized in most other subgroups studied. Cross-sectional analyses. Data from 93 028 children were analyzed. Ov/ob prevalence was significantly higher in 2004 compared with 2000 in girls aged 12-16 years and in boys aged 8-16 years. Ov/ob obesity prevalence was significantly lower in 2008 compared with 2004 in children aged 4-7.99 years. CONCLUSION Ov/ob prevalence increased between 1999 and 2003 in German children. Since 2004, this trend has been stabilizing or turning into a downward trend. Our data confirm the global trend of stabilizing prevalence rates of childhood obesity at a high level and add important information for individual age groups. Intervention programs targeted to prevent childhood obesity may have had beneficial effects, and a new balance between factors favouring obesity and those favouring leanness may have been reached recently. Age- and gender-specific differences found in trends of ov/ob prevalence may help optimise preventive and therapeutic measures.

Combined Effects of Child and Adult Elevated Blood pressure on Subclinical Atherosclerosis: The International Childhood Cardiovascular Cohort Consortium

Background— Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood. Methods and Results— The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ≥90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47–2.38] and 1.57[1.22–2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92–1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50–0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied. Conclusions— Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood.Background— Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood. Methods and Results— The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ≥90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47–2.38] and 1.57[1.22–2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92–1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50–0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied. Conclusions— Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood. # Clinical Perspective {#article-title-39}

Saturated fatty acids induce insulin resistance in human podocytes: implications for diabetic nephropathy

BACKGROUND Cellular insulin resistance is the hallmark of type 2 diabetes and predominantly affects adipose and muscle cells. The saturated free fatty acid palmitate is elevated in insulin-resistant states and may directly contribute to cellular insulin resistance. A spectrum of renal disease is associated with increased markers of insulin resistance, although direct causal mechanisms are not known. In the kidney, glomerular podocytes are novel insulin-sensitive cells that have the ability to rapidly transport glucose. In this study, we tested the hypothesis that palmitate would induce insulin resistance in podocytes. METHODS Conditionally immortalized human podocytes were cultured for up to 24 h with 375-750 muM palmitate. Functional effects on glucose uptake and ceramide production were measured. Gene expression was investigated using a focused gene array, and protein signalling and trafficking were studied with Western blotting and immunofluorescence. RESULTS We found that palmitate blocked insulin-stimulated glucose uptake in human podocytes. This was associated with increased ceramide production, and use of the ceramide inhibitors myriocin and fumonisin B1 partially recovered the insulin sensitivity. At the level of transcription, palmitate downregulated genes associated with several pathways involved in insulin signalling. At the protein level, phosphorylation of the insulin receptor, IRS1 and PKB was reduced and there was impaired translocation of GLUT4 to the cell surface. CONCLUSION This is the first study to demonstrate a direct effect of saturated fatty acids on podocyte function. These findings may represent a novel link between systemic insulin resistance and the development of nephropathy.

Effects of obesity on human sexual development

Puberty is a period of physical and psychological maturation, with long-term effects on health. During the 20th century, a secular trend towards earlier puberty occurred in association with improvements in nutrition. The worldwide pandemic of childhood obesity has renewed interest in the relationship between body composition in childhood and the timing and tempo of puberty. Limited evidence suggests that earlier puberty is associated with a tendency towards central fat deposition; therefore, pubertal status needs to be carefully considered in the categorization of childhood and adolescent overweight and obesity. In the other direction, rapid early weight gain is associated with advanced puberty in both sexes, and a clear association exists between increasing BMI and earlier pubertal development in girls. Evidence in boys is less clear, with the majority of studies showing obesity to be associated with earlier puberty and voice break, although a subgroup of boys with obesity exhibits late puberty, perhaps as a variation of constitutional delay in growth and puberty. The possible mechanisms linking adiposity with pubertal timing are numerous, but leptin, adipocytokines and gut peptides are central players. Other possible mediators include genetic variation and environmental factors such as endocrine disrupting chemicals. This Review presents current evidence on this topic, highlighting inconsistencies and opportunities for future research.

A diagnosis of the metabolic syndrome in youth that resolves by adult life is associated with a normalization of high carotid intima-media thickness and type 2 diabetes mellitus risk: the Bogalusa heart and cardiovascular risk in young Finns studies.

OBJECTIVES The aim of this study was to examine the effect of resolution from metabolic syndrome (MetS) between youth and adulthood on carotid artery intima-media thickness (IMT) and type 2 diabetes mellitus (T2DM). BACKGROUND Published findings demonstrate that youth with MetS are at increased risk of cardio-metabolic outcomes in adulthood. It is not known whether this risk is attenuated in those who resolve their MetS status. METHODS Participants (n = 1,757) from 2 prospective cohort studies were examined as youth (when 9 to 18 years of age) and re-examined 14 to 27 years later. The presence of any 3 components (low high-density lipoprotein cholesterol, high triglycerides, high glucose, high blood pressure, or high body mass index) previously shown to predict adult outcomes defined youth MetS; the harmonized MetS criteria defined adulthood MetS. Participants were classified according to their MetS status at baseline and follow-up and examined for risk of high IMT and T2DM. RESULTS Those with MetS in youth and adulthood were at 3.4 times the risk (95% confidence interval: 2.4 to 4.9) of high IMT and 12.2 times the risk (95% confidence interval: 6.3 to 23.9) of T2DM in adulthood compared with those that did not have MetS at either time-point, whereas those that had resolved their youth MetS status by adulthood showed similar risk to those that did not have MetS at either time-point (p > 0.20 for all comparisons). CONCLUSIONS Although youth with MetS are at increased risk of adult high IMT and T2DM, these data indicate that the resolution of youth MetS by adulthood can go some way to normalize this risk to levels seen in those who have never had MetS.

Fatty acid‐induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid

The elevation of free fatty acids (FFAs), observed in childhood obesity results in intramyocellular lipid (IMCL) accumulation with consequent insulin resistance. Using in vitro differentiated myotubes from normal weight pre‐pubertal children (n = 8), we examined the effects of saturated (palmitate) and unsaturated (oleate) FFAs on insulin‐stimulated AKT phosphorylation (pAKT) and IMCL accumulation. Palmitate decreased pAKT (Mean [SEM] % change pAKT with palmitate 750 µM vs. control; pThr308 site −50.5% [28.7] and pSer473 site −38.7% [11.7]; P < 0.001) with no effect on IMCL formation. Equimolar bromopalmitate did not effect pAKT and blocking ceramide production abolished the palmitate‐induced reduction in signalling, suggesting that ceramide synthesis is critical for palmitates actions. Oleate did not effect pAKT (1,000 µM oleate; pSer473 site −3.4% [11.4]; P = NS) but increased IMCL accumulation (+32.3% [7.1%]; P < 0.001). Co‐administration of oleate diminished the reduction in pAKT seen with palmitate (+36.4% [23.6] vs. −13.3% [13.6]; P = 0.28), with similar IMCL levels to oleate alone. Co‐administration also caused a significant reduction in 14C‐ceramide synthesis from 14C‐palmitate (101.6 [21.6] vs. 371.5 [122.4] DPM/mg protein; P < 0.001). In summary, palmitate appears to cause insulin resistance in childrens myotubes via its metabolism to ceramide, and this process appears unrelated to IMCL formation and is ameliorated by oleate. J. Cell. Physiol. 211: 244–252, 2007.

Characterization of differentiated subcutaneous and visceral adipose tissue from children: the influences of TNF-alpha and IGF-I

The relationship between subcutaneous and visceral adipocyte metabolism and development has been extensively studied in adult but not in pediatric tissue. Our aim was to isolate, develop, characterize, and compare primary cell cultures of subcutaneous and visceral preadipocytes from 16 normal prepubertal children (10 male and 6 female). Subculture techniques were developed to increase cell number and allow differentiation using a chemically defined serum-free medium. Removal of insulin from the differentiation medium prevented adipogenesis in both subcutaneous and visceral preadipocytes, whereas coincubation with rosiglitazone markedly enhanced glycerol-3-phosphate dehydrogenase activity, peroxisome proliferator-activated receptor γ expression, and triglyceride accumulation in cells from both fat depots. Adiponectin secretion increased with differentiation from undetectable levels at day 0. Histological analyses demonstrated significant differences in lipid droplet number and size, with subcutaneous cells having fewer but larger vesicles compared with visceral cells. Downregulation and reorganization of the cytoskeleton appeared comparable. We further demonstrate regional differences in adipogenesis manipulation. Tumor necrosis factor-α was more effective at inhibiting differentiation in subcutaneous cells, whereas insulin-like growth factor-I stimulated differentiation more effectively in visceral cells. Insulin-like growth factor binding protein-3 enhanced differentiation equally. These observations may have important physiological and pharmacological implications for the development of obesity in later life.

Clinical measures of adiposity and percentage fat loss: which measure most accurately reflects fat loss and what should we aim for?

Objective: To determine which clinical measure of childhood obesity should be monitored to best reflect change in adiposity in a weight management programme and estimate the degree of change needed to be relatively certain of fat reduction. Subjects: 92 obese children with a mean (range) age of 12.8 (6.9–18.9) years and a mean body mass index standard deviation score (BMI SDS) of +3.38 (+2.27 to +4.47) attending a hospital-based clinic on a regular, 3 monthly basis. Measurements: Pairs of weight and height measured up to 2.41 years apart used to derive BMI as kg/m2, and adjusted for age and gender to give weight and BMI SDS (BMI-z score) using British 1990 Growth Reference Data. Contemporaneous adiposity estimated by fatness measured by a bioimpedance segmental body composition analyser. Results: Changes in BMI-z scores, compared to BMI, weight and weight SDS, most accurately reflected loss of fat. Reductions of 0.25, 0.5, 0.75, and 1 BMI SDS equate to expected mean falls in total body fat percentage of 2.9%, 5.8%, 8.7% and 11.6%. Approximate 95% prediction intervals indicated that a fall in BMI SDS of at least 0.6 over 6–12 months (or 0.5 over 0–6 months) is consistent with actual fat loss. Conclusion: Change in BMI-z score best reflects percentage fat loss compared to BMI, weight and weight SDS. The wide variation in likely percentage fat loss for a given BMI SDS reduction means a loss of 0.5–0.6 is required to be relatively certain of definite percentage fat reduction.