An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children.

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10-23) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10-16), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children.

Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort.

OBJECTIVES: Adolescent extreme obesity is associated with somatic and psychiatric comorbidity, low quality of life, and social dysfunction. Nevertheless, few adolescents seek obesity treatment, thus many may elope appropriate care. We examine whether previous treatment seeking relates to disease burden, and whether previously non-treatment seeking adolescents accept diagnostic and therapeutic offers. This information is important to inform intervention strategies. METHODS: The Youth with Extreme obesity Study (YES) is a prospective, multicenter cohort study. We developed a novel recruitment strategy to span medical and vocational ascertainment settings and directly compare previously treatment seeking and non-treatment seeking youth. Participants aged 14-24 years; BMI ≥ 30 kg/m2 were enrolled at four medical- and one job centers. We present comorbidity and psycho-social baseline data by sex, obesity WHO grade I-III, and treatment-seeking status, defined as self-reported previous participation in a weight-loss program. RESULTS: Of 431 participants, 47% were male; mean age 16.6 (standard deviation 2.3) years, BMI 39.2 (7.5) kg/m2. Somatic comorbidity increased with obesity grade, p < 0.05: hypertension (42, 55, 64%), dyslipidemia (28, 24, 37%,), dysglycemia (9, 19, 20%,), elevated transaminases (15, 26, 30%). Quality of life (EQ5 D) decreased (74, 71, 70). Rates of psychiatric disorders were stable: depression 11%, attention deficit disorder 6%, substance use disorder 2%, self-injurious behavior 5%, suicide attempt 3%. Only 63% (56, 64, 69%) reported previous treatment seeking. Acceptance of the diagnostic (89%) or therapeutic (28%) program, medical or psychosocial situation did not differ by treatment seeking status. Acceptance of the therapeutic program was generally low, but high at the job center (92%). CONCLUSION: Irrespective of previous treatment seeking, adolescent extreme obesity was associated with high comorbidity and psychosocial burden. Acceptance of the diagnostic program overall and the therapeutic program at the job center were high. This underscores the need of innovative, accessible programs beyond the currently offered care.

Current Guidelines for Obesity Prevention in Childhood and Adolescence.

OBJECTIVE: Current guidelines for prevention of obesity in childhood and adolescence are discussed. METHODS: A literature search was performed in Medline via PubMed, and appropriate studies were analyzed. RESULTS: Programs to prevent childhood obesity have so far remained mainly school-based and effects have been limited. Analyses by age group show that prevention programs have the best results in younger children (<12 years). Evidence-based recommendations for pre-school- and early school-aged children indicate the need for interventions that address parents and teachers alike. During adolescence, school-based interventions proved most effective when adolescents were addressed directly. To date, obesity prevention programs have mainly focused on behavior-oriented prevention. Recommendations for community- or environment-based prevention have been suggested by the German Alliance of Noncommunicable Diseases and include a minimum of 1 h of physical activity at school, promotion of healthy food choices by taxing unhealthy foods, mandatory standards for meals at kindergartens and schools as well as a ban on unhealthy food advertisement aimed at children. CONCLUSION: Behavior-oriented prevention programs showed only limited long-term effects. Certain groups at risk for the development of obesity are not reached effectively by current programs. Although universally valid conclusions cannot be drawn given the heterogeneity of available studies, clearly combining behavior-based programs with community-based prevention to counteract an 'obesogenic environment' is crucial for sustainable success of future obesity prevention programs.

Changes in Satiety Hormones in Response to Leptin Treatment in a Patient with Leptin Deficiency.

BACKGROUND: We tested whether leptin treatment affects secretion of satiety-related gut peptides and brain-derived neurotrophic factor (BDNF), which is a regulator of energy homeostasis downstream of hypothalamic leptin signaling. METHODS: We report the case of a morbidly obese 14.7-year-old girl with a novel previously reported homozygous leptin gene mutation, in whom hormone secretion was evaluated in 30-min intervals for 10 h (07.30-17.30) to assess BDNF, insulin, glucagon-like peptide-1 (GLP-1), ghrelin, and peptide YY (PYY) secretion before as well as 11 and 46 weeks after start of metreleptin treatment. RESULTS: Leptin substitution resulted in strong reductions of body fat and calorie intake. Insulin secretion increased by 58.9% after 11 weeks, but was reduced by -44.8% after 46 weeks compared to baseline. Similarly, GLP-1 increased after 11 weeks (+15.2%) and decreased after 46 weeks. PYY increased consistently (+5%/ +13.2%, after 11/46 weeks). Ghrelin decreased after 46 weeks (-11%). BDNF secretion was not affected by leptin treatment. CONCLUSION: The strong increase in insulin and GLP-1 secretion after 11 weeks of metreleptin treatment cannot be explained by reduced adiposity and might contribute to improved central satiety. Observed changes of PYY can lead to increased satiety as well. However, leptin replacement does not seem to affect circulating BDNF levels.

A Structured, Manual-Based Low-Level Intervention vs. Treatment as Usual Evaluated in a Randomized Controlled Trial for Adolescents with Extreme Obesity - the STEREO Trial.

BACKGROUND: To compare efficacy and safety of a manual-based low-level psychological intervention with treatment as usual (weight loss treatment). METHODS: A two-armed randomized controlled trial without blinding and computer-based stratified block randomization included adolescents and young adults (14.0-24.9 years) with a BMI ≥ 30 kg/m2 at five German university hospitals. Primary outcomes were adherence (participation rate ≥ 5/6 sessions) and quality of life (DISABKIDS-37) 6 months after randomization. Secondary outcomes included depression, self-esteem, and perceived stress scores. RESULTS: Of 397 screened adolescents, 119 (mean BMI 40.4 ± 7.0 kg/m2, 49.6% female) were randomized to the manual-based low-level intervention (n = 59) or treatment as usual (n = 60). We observed no group difference for adherence (absolute risk reduction 0.4%, 95% CI -14.7% to 15.5%; p = 1.0) or health-related quality of life (score difference 8.1, 95% CI -2.1 to 18.3; p = 0.11). Among all secondary outcomes, we detected explorative evidence for an effect on the DISABKIDS-37 'social exclusion' subscale (score difference 15.5; 95% CI 1.6-29.4; p = 0.03). 18/19 adverse events occurred in 26 participants, none were classified as serious. CONCLUSION: Adherence to a coping-oriented intervention was comparable to weight loss treatment, although it was weak in both interventions. Psychological interventions may help to overcome social isolation; further confirmation is required.

Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children.

BACKGROUND: Leptin and adiponectin communicate with organ systems in order to regulate energetic and metabolic homeostasis. Their different points of action have been well characterized; however, no study has investigated their interrelationship with the metabolism at the molecular level in vivo. OBJECTIVE: To examine the associations of leptin and adiponectin with the metabolic profile reflecting the intercellular and interorgan communication as well as activated metabolic pathways. PATIENTS/METHODS: We measured plasma concentrations of leptin, adiponectin, and insulin along with concentrations of 196 metabolites in 400 healthy, fasting 8-years old German children who participated in the German Ulm Birth Cohort Study (UBCS). Using multiple linear mixed models, we evaluated the associations between hormones and metabolites. RESULTS: Leptin levels increased exponentially with increasing BMI. Leptin was furthermore strongly associated with alanine and aspartate (Bonferroni corrected P[PBF] = 5.7×10-8 and 1.7×10-6, respectively), and negatively associated to the sum of the non-esterified fatty acids (NEFA) and the sum of the long-chain acylcarnitines C12-C18 (PBF = 0.009 and 0.0001, respectively). Insulin showed a similar association pattern, although the associations were less strong than for leptin. Adiponectin was neither related to BMI nor to any metabolite. CONCLUSION: Although children were presumably metabolically similar, we found strong associations of insulin and leptin with the metabolite profile. High alanine concentrations and the lower concentrations of NEFA in children with high fasting leptin concentrations might arise from an increased gluconeogenesis and from the disinhibiting effect of leptin on the carnitine-palmitoyltransferase-1, respectively. As insulin had the same trend towards these associations, both hormones seem to be related to processes that provide the body with energy in fasting state.

Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency.

CONTEXT AND AIMS: Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency. METHODS: An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents. RESULTS: In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80-1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48-0.55) being distinct from normal was observed. CONCLUSIONS: The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.

Sonographically Assessed Intra-Abdominal Fat And Cardiometabolic Risk Factors in Adolescents with Extreme Obesity.

OBJECTIVE: The metabolic and cardiovascular risk of obesity is predominantly defined through the amount of intra-abdominal fat (IAF). Regarding this risk and the benefits of weight reduction gender-specific differences have been described. The aim of this study was to examine the gender-specific relationship between IAF assessed via ultrasound and the cardiometabolic risk profile in extremely obese adolescents before and after weight loss. METHODS: In 107 consecutively admitted adolescents (n = 59 girls, mean age 15.4 ± 2.6 years boys and 15.1 ± 2.1 years girls, mean BMI z-score 3.2 ± 0.6 boys and 3.5 ± 0.6 girls) anthropometric and fasting laboratory chemical parameters were measured before and after an in-patient long-term therapy (mean durance 5.6 ± 2.3 months). IAF was determined by measuring the intra-abdominal depth (IAD) via ultrasound. RESULTS: IAD was higher in boys as compared to girls (58.0 ± 22.4 mm vs. 51.3 ± 16.0 mm). IAD values were positively associated with BMI-z scores, waist circumferences, HOMA-IR and serum levels of x03B3;GT, hs-CRP and IL-6 in both genders. In boys, but not in girls, IAD was significantly correlated with systolic and diastolic blood pressure, serum levels of triglycerides, ALT as well as adiponectin and HDL-cholesterol. After a marked mean weight loss of -27.1 ± 16.2 kg (-20.1 ± 7.9%) in boys and of -20.5 ± 11.5 kg (-17.3 ± 7.1%) in girls, IAD decreased by -20.7 ± 16.2 mm (--32.4 ± 16.9%) in boys and by -18.4 ± 12,7 mm (-34.3 ± 18.4%) in girls, resulting in more pronounced ameliorations of cardiovascular risk factors in boys than in girls. CONCLUSIONS: The present study indicates that IAF assessed by ultrasound is a good indicator for the cardiometabolic risk factor profile in extremely obese adolescents. Associations between IAF and risk factors are more pronounced in boys than in girls.

Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene.

CONTEXT: Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone. CASE DESCRIPTION: We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss. CONCLUSIONS: Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.

Intrafamilial associations of cardiometabolic risk factors--results of the Ulm Birth Cohort Study.

BACKGROUND: The identification of genetic, early childhood and lifestyle factors related to cardiometabolic risk factors in childhood is important for the development of preventive strategies against cardiovascular diseases. Intrafamilial associations of cardiometabolic risk factors are rarely studied and the few existing results are inconsistent. AIMS: To study the relationship of cardiometabolic risk factors in parent-offspring pairs (trios) of the prospective Ulm Birth Cohort Study (UBCS). METHODS: At the 8-yr follow-up examination of the UBCS weights, heights, waist circumferences (WC), systolic (sysBP) and diastolic blood pressure (diasBP) of n=304 8 yrs old children and their parents were measured. Fasting plasma samples were collected and concentrations of insulin, glucose, retinol-binding-protein 4 (RBP4), adiponectin, leptin, apolipoprotein A and B (ApoA, ApoB) were analyzed. RESULTS: BMI values and WC were stronger related in father-offspring than in mother-offspring pairs. Adjustment for potential confounders did not change these results. Fasting plasma concentrations of insulin, glucose, RBP4, ApoB, sysBP and diastBP were stronger correlated in mother-offspring than in father-offspring pairs also after adjusting for potential confounders. Offsprings of fathers that have ≥3 cardiometabolic risk factors had 0.74 kg/m2 higher BMI values and 2.34 cm higher WC compared to offsprings of the reference group (both parents having <3 cardiometabolic risk factors). There was a trend for higher fasting plasma insulin concentrations in offsprings where the mother had ≥3 cardiometabolic risk factors compared to offsprings of the reference group. CONCLUSION: These results might be explained by gender-specific genetic factors as well as by early life programming.

Weight loss in children and adolescents.

BACKGROUND: 15% of children and adolescents in Germany are overweight, including 6.3% who are affected by obesity. The efficacy of conservative weight-loss treatments has been demonstrated, but there has not yet been a detailed analysis of their efficacy in terms of the amount of weight loss that can be expected. We re-evaluated the available evidence on this question, with particular attention to the methodological quality of clinical trials, in order to derive information that might be a useful guide for treatment. METHODS: We conducted a systematic literature search of Medline for the period May 2008 (final inclusion date for a 2009 Cochrane Review) to December 2013. The identified studies were analyzed qualitatively. RESULTS: 48 randomized controlled clinical trials with a total of 5025 participants met the predefined inclusion criteria for this analysis. In the ones that met predefined criteria for methodological quality, conservative weight-loss treatments led to weight loss in amounts ranging from 0.05 to 0.42 BMI z score (standard deviation score of the body mass index) over a period of 12-24 months. Information on trial dropout rates was available for 41 of the 48 trials; the dropout rate was 10% or higher in 27 of these (66% ), and 25% or higher in 9 (22% ). CONCLUSION: The available evidence consistently shows that only a modest degree of weight loss can be expected from conservative treatment. Families seeking treatment should be informed of this fact. Future research should focus on determining predictive factors for therapeutic benefit, and on the evaluation of additional types of psychological intervention to promote coping with obesity.

Restrained and external-emotional eating patterns in young overweight children-results of the Ulm Birth Cohort Study.

Childhood obesity is one of the greatest public health challenges in Western countries. Abnormal eating behavior is thought to be a developmental trajectory to obesity. The Eating Pattern Inventory for Children (EPI-C) has not been used for children as young as eight years, and possible associations with body weight have not yet been established. Five hundred and twenty-one children of the Ulm Birth Cohort Study (UBCS; age eight) filled out the EPI-C and BMI was assessed. Adequacy of the scales was tested with confirmatory factor analysis and a MANOVA and cluster analysis established associations between eating patterns and BMI. The factor structure of the EPI-C was confirmed (GFI = .968) and abnormal eating behavior was associated with overweight (χ(2)(8) =79.29, p<.001). The EPI-C is a valid assessment tool in this young age group. Overweight children consciously restrain their eating.

Unexpected plateauing of childhood obesity rates in developed countries.

Surveys performed in the past 10 to 15 years show a yet unexplained stabilization or decline in prevalence rates of childhood obesity in developed countries. The projected continuous increase in obesity prevalence throughout future decades seems not to occur at present. Apparently, saturation has been reached, which might be related to societal adjustments. Hence, we postulate a cumulative effect of public health programs for obesity prevention resulting, for example, in an increase in physical activity, and a decline in television viewing and in the consumption of sugar-sweetened soft drinks by children. Effective public health programs are urgently needed for developing countries, where obesity rates in children still continued to increase during the past decade.

Plasma insulin levels in childhood are related to maternal factors--results of the Ulm Birth Cohort Study.

AIMS: The cardiovascular risk factor profile of a child as well as the development of body weight are influenced by genetic and childhood factors. Circulating insulin concentrations reflect the metabolic cardiovascular risk and may trigger weight gain. We aimed at identifying parental and childhood factors which may influence fasting plasma insulin concentrations in children. METHODS: The Ulm Birth Cohort study (UBCS) is a prospective birth cohort study. At baseline, birth characteristics, maternal pre-pregnancy body mass index (BMI) values as well as parental socioeconomic parameters were obtained. At the 8-yr follow-up examination, weights, heights, and fasting plasma insulin concentrations in n = 422 children and their parents were measured. Offspring of women with gestational diabetes mellitus were excluded from statistical analysis. RESULTS: Fasting plasma insulin concentrations of children were significantly correlated with maternal pre-pregnancy BMI values (r = 0.16) as well as with maternal (r = 0.26) but not with paternal fasting plasma insulin concentrations (r = 0.11) at the 8-yr follow-up examination. The risk for high fasting plasma insulin concentrations (≥75th internal percentile) was 2.30 (1.34-3.92) in children who also had high plasma insulin concentrations in umbilical cord blood compared to children having lower plasma insulin concentrations (<75th internal percentile) in umbilical cord blood. In addition, we observed that children with high fasting plasma insulin concentrations at the age of 8 had an altered BMI trajectory in childhood, characterized by higher BMI values from the age of 1 onwards, compared to children with lower insulin concentrations. CONCLUSION: Our observations support the hypothesis of perinatal programming of offspring insulin concentrations and BMI values by maternal pre-pregnancy BMI values.

Medical and psychosocial implications of adolescent extreme obesity - acceptance and effects of structured care, short: Youth with Extreme Obesity Study (YES).

BACKGROUND: Prevalence rates of overweight and obesity have increased in German children and adolescents in the last three decades. Adolescents with extreme obesity represent a distinct risk group. On the basis of data obtained by the German Child and Youth Survey (KiGGS) and the German district military offices we estimate that the group of extremely obese adolescents (BMI ≥ 35 kg/m2) currently encompasses approximately 200.000 adolescents aged 14 to 21 yrs. Conventional approaches focusing on weight reduction have largely proven futile for them. In addition, only a small percentage of adolescents with extreme obesity seek actively treatment for obesity while contributing disproportionately strong to health care costs. Because of somatic and psychiatric co-morbidities and social problems adolescents with extreme obesity require special attention within the medical care system. We have initiated the project "Medical and psychosocial implications of adolescents with extreme obesity--acceptance and effects of structured care, short: 'Youths with Extreme Obesity Study (YES)'", which aims at improving the medical care and social support structures for youths with extreme obesity in Germany. METHODS/DESIGN: We focus on identification of these subjects (baseline examination) and their acceptance of diagnostic and subsequent treatment procedures. In a randomized controlled trial (RCT) we will investigate the effectiveness of a low key group intervention not focusing on weight loss but aimed at the provision of obesity related information, alleviation of social isolation, school and vocational integration and improvement of self-esteem in comparison to a control group treated in a conventional way with focus on weight loss. Interested individuals who fulfill current recommended criteria for weight loss surgery will be provided with a structured preparation and follow-up programs. All subjects will be monitored within a long-term observational study to elucidate medical and psychosocial outcomes. Our aim is to evaluate realistic treatment options. Therefore inclusion and exclusion criteria are minimized. We will recruit adolescents (age range 14-21 years) with extreme obesity (BMI ≥ 35 kg/m2) (extreme group) within 24 months (120 per centre, 5 centres) as well as obese adolescents being at risk for developing extreme obesity (BMI ≥ 30-34.9 kg/m2) (at risk group). Follow-up evalutations will be performed biannually after inclusion for several years depending on additional funding. In sum, we aim at establishing evaluated health care structures for extremely obese adolescents. DISCUSSION: The results of YES will be of importance for a frequently neglected group of individuals, for whom current medicine has little to offer in terms of structured access to empirically evaluated therapeutic programs. Thus, the results will be both a help for the adolescents within the study and for others in the future given that the trial will lead to a positive finding. Moreover, it will help practitioners and therapists to deal with this neglected group of individuals. TRIAL REGISTRATION: Project registration numbers for each subproject: 1.) ClinicalTrials.gov: NCT01625325, NCT01703273, NCT01662271, NCT01632098; 2.) Germanctr.de: DRKS00004172, DRKS00004195, DRKS00004198, DRKS00004197.

Impaired HDL function in obese adolescents: impact of lifestyle intervention and bariatric surgery.

OBJECTIVE: HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL-mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-ßII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-ßII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-ßII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction.

Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient.

CONTEXT: Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy. DESIGN, PATIENT: Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient. RESULTS: The comparison of 'food vs. non-food' pictures showed a stabilization of the long-term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions. CONCLUSION: This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency.

Silent slipped capital femoral epiphysis in overweight and obese children and adolescents.

Abnormal loading of the hip in obese children may lead to anatomic alterations and an increased prevalence of slipped capital femoral epiphysis (SCFE). The aims of this study were to examine the hip motion in obese children and adolescents and to estimate the prevalence of SCFE in a subgroup of patients characterized by pathological clinical examination and/or pain in the knee or hip joint. A total of 411 individuals (196 males), mean age 14.5 ± 2.5 years (7.8-20.4), mean BMI of 32.9 ± 5.6 kg/m(2) (20.3-51.5, z score +2.65) who were consecutively admitted for an inpatient weight loss program were included in the study. Twenty-six percent of the patients had load-dependent and 11.7 % had load-independent pain in the knee joint. A total of 9.3 % had load-dependent and 4.7 % had load-independent pain in the hip joint. Two patients (0.5 %) underwent surgical treatment of SCFE prior to entry. A total of 18.2 % of the patients showed a reduced range of motion for hip flexion (<90°) and 18.5 % a pathological decreased internal rotation (<10°). Radiological evaluation of the hips in the clinically conspicuous subgroup (n = 54) revealed an abnormal head-neck ratio as a sign of prior silent slipped capital femoral epiphysis in 11 patients (20.4 % of the 54 patients, 2.7 % of total cohort). In conclusion, these data show a high prevalence of SCFE-like tilt deformities in a selected group of severely obese children. Mild deformation of the epiphysis at young age might be a major predisposing factor for the development of hip osteoarthritis in obese adults.

Declining prevalence rates for overweight and obesity in German children starting school.

UNLABELLED: To estimate the development of prevalence rates for overweight and obesity in children starting school in Germany, data for children's height and weight out of the compulsory school enrolment examinations (SEE), conducted annually in every German federal state, were available. A former analysis of these data showed a marked increase of prevalence of overweight and obesity until 2004. The aim of this project was to give an updated overview on the development of prevalence rates for overweight and obesity in children upon school entry by including recent data until 2008. Data on measured height and weight from the yearly conducted SEE were obtained from all 16 German federal states. Overweight and obesity were defined by BMI > 90th and BMI > 97th age- and gender-related percentiles of German reference values, respectively. In 2008, the prevalence for overweight varied from 8.4% in Saxony to 11.9% in Bremen and Thuringia. The current prevalence rates for obesity ranged from 3.3% in Brandenburg and Saxony till 5.4% in Saarland. The current data from SEE by the majority of the individual states showed that the prevalence for both overweight and obesity did not increase any more after 2004 and is even declining in some states compared to the former data inquiry. Absolute decrease of prevalence rates was up to 3% for overweight and 1.8% for obesity. CONCLUSION: The current data from the SEE of individual German states are based on census and showed by the majority that the prevalence of overweight and obese children starting school did not increase anymore and even declined in the last 4 years, respectively. It is supposed that the measures for prevention initiated in the 1990s and implemented afterwards have contributed to this positive development in Germany.

Leptin therapy in a congenital leptin-deficient patient leads to acute and long-term changes in homeostatic, reward, and food-related brain areas.

CONTEXT: Mutations that lead to congenital leptin deficiency cause severe obesity, hyperphagia, and impaired satiety due to malfunctions of peripheral and brain-related mechanisms. DESIGN AND PATIENT: In a leptin-deficient adolescent girl, we investigated brain-related changes before and at two time points after leptin therapy (3 d and 6 months). Functional magnetic resonance imaging was performed during visual stimulation with food (high and low caloric) and nonfood pictures. RESULTS: Results show acute and long-term effects in the amygdala, the orbitofrontal cortex, and the substantia nigra/ventral tegmental area for the comparison of food and nonfood pictures. For the comparison of high and low caloric pictures, pure acute effects in the ventral striatum and the orbitofrontal cortex could be observed as well as acute and long-term effects in the hypothalamus. CONCLUSION: This study gives additional insight in the influence of leptin therapy on brain functions in leptin deficiency.