Johannes Hebebrand

Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutscher Stichproben

ZusammenfassungFragestellung. Sowohl die Childhood Group der International Obesity Task Force (IOTF) als auch die European Childhood Obesity Group (ECOG) empfehlen den Body-mass-Index als Beurteilungskriterium für Übergewicht und Adipositas bei Kindern und Jugendlichen. Im Erwachsenenalter erfolgt die Definition von Übergewicht und Adipositas anhand fester Grenzwerte, bei der Beurteilung von Kindern und Jugendlichen müssen die alters- und geschlechtsspezifischen Veränderungen des BMI berücksichtigt werden. Methode. Unter Heranziehung von 17 bereits durchgeführten Untersuchungen aus verschiedenen Regionen Deutschlands wurden BMI-Perzentile für Kinder und Jugendliche erstellt. Die Berechnung der Perzentile basiert auf den Körperhöhen- und Körpergewichtsdaten von 17.147 Jungen und 17.275 Mädchen im Alter von 0–18 Jahren. Ergebnisse und Schlussfolgerung. Die vorgestellten Perzentile sollten als Referenz für deutsche Kinder und Jugendliche angewendet werden. Die Arbeitsgemeinschaft “Adipositas im Kindes- und Jugendalter” (AGA) hat in ihren Leitlinien die Anwendung der hier vorgestellten 90. und 97. Perzentile zur Definition von Übergewicht und Adipositas empfohlen.AbstractObjectives. Both the Childhood Group of the International Obesity Task Force (IOTF) and the European Childhood Obesity Group (ECOG) recommend to use the body mass index (BMI = weight in kilograms/height in meter2) to evaluate overweight and obesity in children and adolescents. Whereas it is customary with adults to use fixed cut off points to define overweight and obesity, in children and adolescents age and sex specific developmental changes in BMI need to be addressed, which are due to physiological alterations of fat mass. Method. Because a national reference population for children and adolescents does not exist in Germany, a BMI reference data set was compiled. Therefore measurements of height and weight from 17 different regional studies including 17147 boys and 17275 girls aged 0 to 18 years were used. Results and conclusions. We recommend the use of the presented percentiles as reference to asses under- and overweight (obesity) in German children and adolescents. In the guidelines of the “Arbeitsgruppe Adipo-sitas im Kindes- und Jugendalter” (AGA) the 90th and 97th BMI percentiles as calculated in this reference population are proposed as cut-off points for the definition of overweight and obesity in German children and adolescents.

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%–28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants.

Background Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. Methodology/Principal Findings a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p = 1.13×10−7, corrected p = 0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (CI) 1.22–2.27; ORTT 2.76, 95% CI 1.88–4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p<0.01). However, none of the nine non-FTO SNPs revealed significant transmission disequilibrium. Conclusions/Significance Our GWA for extreme early onset obesity substantiates that variation in FTO strongly contributes to early onset obesity. This is a further proof of concept for GWA to detect genes relevant for highly complex phenotypes. We concurrently show that nine additional SNPs with initially low p-values in the GWA were not confirmed in our family study, thus suggesting that of the best 15 SNPs in the GWA only the FTO SNPs represent true positive findings.

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Does obesity surgery improve psychosocial functioning? A systematic review.

OBJECTIVE: The objective of this study is to present a review of the psychosocial outcome of bariatric surgery with special consideration of psychiatric comorbidity, psychopathology, psychosocial functioning, econometric data, and general quality of life (QoL).PURPOSE: A review of all (non-) controlled trials of the last two decades both with a retrospective and prospective design and a follow-up period of at least 1 y.RESEARCH METHODS AND PROCEDURES: The relevant literature was identified by a search of computerized databases. All articles published in English and German since 1980 were reviewed. Based on the requirements of the evidenced-based guidelines of the Agency for Health Care Policy and Research and the Scottish Intercollegiate Guidelines Network, each study was rated by a level of evidence.RESULTS: In all, 171 publications were reviewed. Using the above inclusion/exclusion criteria, 63 articles including two systematic reviews were identified. A total of 40 studies focused on psychosocial outcome after obesity surgery.CONCLUSION: Mental health and psychosocial status including social relations and employment opportunities improve for the majority of people after bariatric surgery thus leading to an improved QoL. Psychiatric comorbidity, predominantly affective disorders, and psychopathologic symptoms decrease postsurgically. A substantial percentage of bariatric surgery patients suffer from binge eating disorder or binge eating symptoms. The effect of bariatric surgery on the outcome of binge eating symptoms largely depends on the type of operation. With the exception of patients with a severe psychiatric comorbidity, the concern that obesity surgery will reinforce psychic symptoms and lead to a reduction in the QoL seems to be unfounded.

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: Alternative biallelic variation in rhesus monkeys

SummaryBy conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter genes 5′-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio. years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and nonhuman primate populations.

Prospective 10‐year Follow‐up in Adolescent Anorexia Nervosa—Course, Outcome, Psychiatric Comorbidity, and Psychosocial Adaptation

The aim of the present study was to follow up the long-term course of adolescent-onset anorexia nervosa by repeated assessment, to analyze the association between the course of the eating disorder and psychiatric comorbidity, and to evaluate psychosocial outcome. The sample consisted of 39 inpatients who were reinvestigated 3, 7, and 10 years after discharge. The patients and 39 controls matched for age, gender, and occupational status were assessed with structured interviews on DSM-III-R eating disorders, additional axis I and axis II psychiatric disorders, and psychosocial functioning. Results showed that 69 % of the original subjects met the criteria for full recovery at the 10-year follow-up. One patient (3%) still exhibited the full syndrome of restrictive anorexia nervosa, two patients (5%) the full syndrome of bulimia nervosa. None of the patients had died. Of the subjects, 51% currently had an axis I psychiatric disorder and 23% met the full criteria for a personality disorder. Apart from the eating disorder, anxiety disorders and avoidant-dependent and obsessive-compulsive personality disorders were the most common psychiatric diagnoses. There was a significant association between psychiatric comorbidity and the outcome of the eating disorder and between outcome and psychosocial adaptation. With regard to psychiatric morbidity and psychosocial functioning, long-term recovered patients did not differ significantly from normal controls. It is concluded that in most patients adolescent anorexia nervosa takes a prolonged course, although it seems to be more favorable than in adult-onset forms. Those who achieve complete recovery from the eating disorder have a good chance of overcoming other psychiatric disorders and to adapt to social requirements.

Social class, parental education, and obesity prevalence in a study of six-year-old children in Germany

OBJECTIVE:To assess the association between socioeconomic status (SES) and childhood obesity, and which factor in particular stands out in relation to obesity.METHODS:When 2020 children attended their obligatory health exam prior to school entry in the City of Aachen, Germany, 1979 parents (97.9%) filled out a questionnaire on their childs weight development and on indicators of their familys SES in a cross-sectional survey. In addition, standardized measures of weight and height were taken. More detailed information on several different SES variables, such as parental education, occupation, income, family constellation, single parenthood, and the location and size of the family residence was obtained by personal interviews in a subsample of all native German speaking children with a BMI≥85th percentile, defined as cases (n=146), and with a BMI between the 40th and 60th percentile, defined as controls (n=221).RESULTS:The indicators of parental education were most strongly associated with childrens obesity. There was a strong dose–response relationship between a composed index of social class and obesity. Children of the lowest social status had a more than three-fold risk to be obese than children of the highest social status in the screening population (OR: 3.29, CI: 1.92–5.63).CONCLUSIONS:The findings established a strong relationship between parental years of education and childhood obesity. Prevention and treatment programs should endeavor to better target undereducated parents and their young children at high risk.

Melanocortin-4 Receptor Gene Variant I103 Is Negatively Associated with Obesity

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.