J. Hebebrand

Rates of psychiatric disorders in a clinical study group of adolescents with extreme obesity and in obese adolescents ascertained via a population based study

OBJECTIVE: To compare rates of DSM-IV psychiatric disorders between (1) a clinical study group of extremely obese adolescents and young adults, (2) gender-matched population-based obese controls and (3) a population-based control group of the same age range.DESIGN: Rates of psychiatric disorders were assessed in (1) the clinical study group of obese adolescents and (2) the population based sample of obese adolescents, and compared to (3) a large population-based control group using a standardized psychiatric interview.SUBJECTS: (1) Clinical study group: 30 female and 17 male extremely obese adolescents and young adults (age range: 15–21u2005y; mean BMI:42.4u2005kg/m2). (2) Thirty females and 17 males with the highest BMI (age range 15–21u2005y; mean BMI:29.8u2005kg/m2) of a population-based control group encompassing 1655 (805 males) adolescents and young adults. (3) The population based control group excluding the 30 females and 17 males with the highest BMI (n=1608; 788 males).MEASUREMENTS: Munich-Composite International Diagnostic Interview (M-CIDI) allowing for DSM-IV diagnoses.RESULTS: High rates of mood, anxiety, somatoform and eating disorders were detected in the clinical sample of obese adolescents which exceeded those observed in population controls (all P-values<0.01). Rates between population-based obese adolescents and young adults and population controls did not differ. In most patients the psychiatric disorders set in after onset of obesity. 57% and 35% of the female and male patients, respectively, reported eating binges with lack of control. However, less than one-half of these patients qualified for a DSM-IV diagnosis of an eating disorder.CONCLUSIONS: Extremely obese adolescents and young adults who seek long-term inpatient treatment have a high lifetime prevalence for affective, anxiety, somatoform and eating disorders. Because the mean BMI of the clinical study group was considerably higher than that of the obese population controls, we were not able to clarify whether the high rate of psychopathology in the study group was related to the extreme obesity or to their treatment-seeking behavior.

Hyperactivity in patients with anorexia nervosa and in semistarved rats: evidence for a pivotal role of hypoleptinemia.

Patients with anorexia nervosa (AN) often show normal to elevated physical activity levels despite severe weight loss and emaciation. This is seemingly in contrast to the loss of energy and fatigue characteristic of other starvation states associated with weight loss. Despite the fact that historical accounts and clinical case studies of AN have regularly commented on the elevated activity levels, the behavior has become only recently the subject of systematic study. Because rodents and other species increase their activity upon food restriction leading to weight loss when given access to an activity wheel--a phenomenon referred to as activity-based anorexia or semi-starvation-induced hyperactivity (SIH)-it has been proposed that the hyperactivity in AN patients may reflect the mobilization of phylogenetically old pathways in individuals predisposed to AN. Exogeneous application of leptin in this animal model of AN has recently been shown to suppress completely the development of SIH. Hypoleptinemia, as a result of the food restriction, may represent the initial trigger for the increased activity levels in AN patients and in food-restricted rats. In the first and second parts of our review, we will summarize the relevant findings pertaining to hyperactivity in AN patients and in the rat model, respectively. We conclude with a synopsis and implications for future research.

Leptin suppresses semi-starvation induced hyperactivity in rats: implications for anorexia nervosa

Semi-starvation induced hyperactivity (SIH) occurs in rodents upon caloric restriction. We hypothesized that SIH is triggered by the decline in leptin secretion associated with food restriction. To test this hypothesis, rats, which had established a stable level of activity, were treated with leptin or vehicle via implanted minipumps concomitantly to initiation of food restriction for 7 days. In a second experiment treatment was initiated after SIH had already set in. In contrast to the vehicle-treated rats, which increased their baseline activity level by 300%, the development of SIH was suppressed by leptin. Furthermore, leptin was able to stop SIH, after it had set in. These results underscore the assumed major role of leptin in the adaptation to semi-starvation. Because SIH has been viewed as a model for anorexia nervosa, we also assessed subjective ratings of motor restlessness in 30 patients with this eating disorder in the emaciated state associated with hypoleptinemia and after increments in leptin secretion brought upon by therapeutically induced weight gain. Hypoleptinemic patients ranked their motor restlessness higher than upon attainment of their maximal leptin level during inpatient treatment. Thus, hypoleptinemia might also contribute to the hyperactivity frequently associated with anorexia nervosa.

Serotonin transporter gene-linked polymorphic region: Allele distributions in relationship to body weight and in anorexia nervosa

Several lines of evidence implicate a role for the serotonergic system in body weight regulation and eating disorders. The magnitude and duration of postsynaptic responses to serotonin (5-HT) is directed by the transport into and release from the presynaptic neuron. Recently, a common polymorphism of a repetitive element in the region of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) was identified that results in a system of two common alleles. The activity of the 5-HTT, as measured in in vitro assays and in human lymphoblastoid cell lines, is dependent on the respective genotype. We thus hypothesized that this polymorphism is relevant for weight regulation in general and is possibly involved in the etiology of anorexia nervosa (AN). Allele frequencies and genotypes were determined in a total of 385 unrelated obese children, adolescents and adults, 112 underweight subjects and 96 patients with AN. Furthermore, both parents of 98 obese children and adolescents and of 55 patients with AN, respectively, were genotyped, thus allowing to test for both association and linkage. The comparison of allele frequencies between obese and underweight probands provided no evidence for a major role of the 5-HTTLPR in weight regulation. Patients with AN had allele frequencies not significantly different to those observed for obese and underweight individuals.

Epidemic obesity: are genetic factors involved via increased rates of assortative mating?

OBJECTIVE: Prevalence rates of obesity have been increasing in several countries over the past two decades. Mainly secular changes in energy intake and expenditure have been invoked to underly the increasing rates; genetic factors have not been considered because of the very recency of this phenomenon. We hypothesize that genetic factors might very well be involved via an increased rate of assortative mating between obese individuals. We speculate that the recent upsurge in social stigmatization of obese individuals underlies the hypothesized increase in assortative mating.DESIGN: To accumulate evidence for our hypothesis we analysed deduced rates of assortative mating among parents of extremely obese children and adolescents, who belonged to two different large study groups (n=201 and n=270). For this purpose we calculated parental body mass indices (BMIs) based on (a) measured current heights and weights, (b) self-reported current heights and weights, and finally (c) measured current heights and recalled weights at ages 20 and 30, respectively. BMI centiles were determined which in turn were attributed to the respective BMI decile. Deduced rates of assortative mating were evaluated in bivariate histograms of the paternal and maternal BMI deciles.RESULTS: High rates of assortative mating were observed as deduced from the bivariate histograms, which revealed a fairly consistent pattern. Thus, in the first study group almost 35% of the parental pairs had a BMI in the tenth decile; over 50% of the mothers and fathers had a BMI in this top decile. Recalled parental BMIs at ages 20 and 30 also clustered in the upper decile. These results were basically replicated in the second study group. In addition, parental loading on the tenth decile was shown to be higher for the subgroup of children and adolescents who had a BMI equal to or exceeding the highest BMI of the population-based age and gender matched control group.CONCLUSIONS: Our results indicate that assortative mating is common among parents of extremely obese children and adolescents, ascertained between 1995 and 1997. In addition, the parental loading on the tenth decile is most prominent for the most obese children. Whereas we are unable to document an increased rate of assortative mating, we interpret our results as being consistent with the hypothesis that an increased rate of assortative mating has contributed to the recent rise in obesity rates in several countries. Thus, assortative mating warrants further studies to assess its impact on obesity prevalence rates through both genetic and non-genetic mechanisms. Our results suggest that assortative mating might especially increase the rates for extreme obesity.

Spectrum of binge eating symptomatology in patients treated with clozapine and olanzapine.

Summary. The authors explored the binge eating symptomatology in 74 patients receiving clozapine (N = 57) or olanzapine (N = 17), and compared body mass index (BMI, kg/m2) and weight gain in patients with and without binge eating symptomatology. Subjects who screened positively for binge eating were interviewed using a modified version of the Questionnaire on Eating and Weight Patterns (QEWP). Current BMIs were assessed cross-sectionally, BMIs at initiation of clozapine/olanzapine treatment retrospectively. Thirty-seven subjects (50%) screened positively. Taking clozapine and olanzapine together, 6/27 (22.2%) females and 3/47 (6.4%) males fulfilled criteria for binge eating disorder, 3/27 (11.1%) females and 2/47 (4.3%) males for bulimia nervosa. Patients who screened positively showed higher current BMIs (26.8 ± 3.9 vs. 24.7 ± 3.7u2009kg/m2) and higher BMI increments during clozapine/olanzapine treatment (3.9 ± 3.1 vs. 2.6 ± 3.4u2009kg/m2) than patients who screened negatively. We conclude that clozapine/olanzapine may induce binge eating and full blown eating disorders which may have predictive value for weight gain. For future research in this field we suggest a novel DSM-IV research classification “Medication-induced eating disorders”.

Serum leptin and gonadotropin levels in patients with anorexia nervosa during weight gain

Leptin plays an important role in reproductive function. In patients with acute anorexia nervosa, serum leptin levels have repeatedly been shown to be lower than in age-matched controls. We have previously hypothesized that the amenorrhea characteristic of anorexia nervosa is related to this low leptin secretion. In an attempt to address this hypothesis, serum levels of leptin and follicle stimulating hormone (FSH) and luteinizing hormone (LH) of 16 female inpatients with anorexia nervosa or an eating disorder not otherwise specified (atypical anorexia nervosa) were measured on a biweekly basis during weight gain. We hypothesized that a serum leptin level of 1.85u2009μgu2009L−1 would be associated with gonadotropin levels at or above the minimal level observed during the menstrual cycle in healthy adult fertile females. Our results revealed that increments of LH levels generally tracked increments of leptin levels during the first weeks of treatment. Similarly, in those patients with low referral leptin levels, FSH initially also tracked leptin levels. In contrast, a relationship between gonadotropin levels and leptin secretion was no longer discernible after LH and FSH levels had peaked. Those patients with exceedingly low leptin levels upon admission revealed a slow increase of gonadotropin levels. Our hypothesis of a threshold leptin level of 1.85u2009μgu2009L−1 was supported for LH only.

β3-adrenergic-receptor allele distributions in children, adolescents and young adults with obesity, underweight or anorexia nervosa

OBJECTIVE: The missense mutation (64Trp to 64Arg) in the Β3-adrenergic-receptor has previously been described to confer a genetic predisposition to the development of obesity. DESIGN: To test the hypothesis we evaluated allele frequencies in children, adolescents and young adults who belonged to different weight groups that were delineated with percentiles for the body mass index (BMI; kg/m2). SUBJECTS: 99 underweight probands (BMI ≤15th percentile). 80 normal weight probands (BMI: 5th–85th percentile). 238 obese children and adolescents (BMI ≥97th percentile). 84 patients with anorexia nervosa (AN). MEASUREMENTS: The cohorts were screened by polymerase chain reaction with subsequent restriction fragment length polymorphism (PCR-RFLP) analysis. Data were statistically analysed for association. In addition to these case control studies, the transmission disequilibrium test (TDT) was applied to 80 families of obese probands and to 52 families of patients with AN. RESULTS: Both the tests for association and linkage were negative. The Trp64Arg allele frequencies in the three weight groups (obesity: 0.071; normal weight: 0.081; underweight: 0.056) and the AN patients (0.054) were similar. Extremely obese individuals showed no excess of the Trp64Arg allele. No homozygotes for the Trp64Arg allele were detected. CONCLUSION: Heterozygosity for the Trp64Arg allele is not of major importance in regulation of body weight in individuals younger than 35xa0y. Additionally, the extreme obese subgroup is not enriched for the polymorphism.

Further lack of association between the 5-HT2A gene promoter polymorphism and susceptibility to eating disorders and a meta-analysis pertaining to anorexia nervosa.

Further lack of association between the 5-HT 2A gene promoter polymorphism and susceptibility to eating disorders and a meta-analysis pertaining to anorexia nervosa

No evidence for involvement of the leptin gene in anorexia nervosa, bulimia nervosa, underweight or early onset extreme obesity: identification of two novel mutations in the coding sequence and a novel polymorphism in the leptin gene linked upstream region

Mutations in the leptin gene can result in profound obesity in both rodents and humans.1–3 In humans, serum leptin levels correlate with body mass index4 (BMI: kgu2009m−2). However, in patients with anorexia nervosa (AN) leptin levels are lower than in BMI-matched healthy controls.5 We had previously argued that genes involved in weight regulation should be considered as candidate genes for AN.6 To investigate this hypothesis we screened the coding region of the leptin gene and part of the leptin gene linked upstream region (LEGLUR) in 49 patients with AN and 315 children and adolescents with extreme obesity. Two novel mutations in the coding region (Ser-91-Ser; Glu-126-Gln), each found in a single proband, and a novel polymorphism in the LEGLUR (position −1387 G/A; frequency of both alleles approximately 0.50) were identified. Tests for association of LEGLUR polymorphism alleles were negative by comparing allele frequencies between 115 AN patients, 71 bulimia nervosa patients, 315 extremely obese children and adolescents, 141 healthy underweights and 50 controls that were not selected for body weight. Tests for transmission disequilibrium were also negative. Hence, an influence of variations in the leptin gene on eating disorders or extreme early onset obesity could not be detected.