The melanocortin-4 receptor gene (MC4-R) has been implicated in weight regulation. Recently, two independent groups reported frameshift mutations associated with a dominant form of obesity (1, 2). We screened the coding region of the MC4-R in 306 extremely obese children and adolescents (mean body mass index: BMI 34.4 +/- 6.6 kg/m2), 25 healthy underweight students (mean BMI 17.1 +/- 0.8 kg/m2), 52 normal weight individuals (mean BMI 22.0 +/- 1.0 kg/m2), 51 inpatients with anorexia nervosa (AN, DSM IV criteria, mean BMI 14.3 +/- 1.5 kg/m2) and 27 patients with bulimia nervosa (BN, DSM IV criteria, mean BMI 21.7 +/- 5.8 kg/m2) by single strand conformation polymorphism analysis (SSCP). Several mutations were identified, including the frameshift mutation described (1). The mutations were as follows: a) The deletion of 4 bp (delta of CTCT at codon 211) results in a frameshift, thus rendering a truncated protein. This mutation has been assumed to be associated with dominantly-inherited morbid obesity in humans (1). Both the index patient (BMI 42.06 kg/m2, height 171 cm, age 19.6 years) and her mother (BMI 37.55 kg/m2, height 164 cm, age 42.5 years) were heterozygous for the deletion. b) A nonsense mutation at position 35 of the MC4-R was detected in two obese probands (BMI 31.29 kg/m2 and BMI 45.91 kg/m2). This mutation leads to a truncated protein that encompasses the N-terminal extracellular domain. Both carriers additionally showed (c) a missense mutation (Asp-37-Val). In both of these cases Tyr-35-Stop and Asp-37-Val were maternally transmitted, thus these variations form a haplotype. d) e) A male obese proband harbored two missense mutations (Ser-30-Phe, Gly-252-Ser). f)-i) Four different missense mutations (Pro-78-Leu, Thr-112-Met, Arg-165-Trp, Ile-317-Thr) were detected in four different male probands, respectively. All of these mutations (a to i) were found solely in extremely obese individuals whose BMIs were all above the 99th percentile. j) A silent mutation (C-579-T, Val-193-Val) was detected in a male underweight individual. k) A previously described polymorphism (Val-103-Ile; 3) was detected with similar frequencies in all different study groups. 1) We identified a novel polymorphism (Ile-251-Leu) with similar allele frequencies in all groups under study. In conclusion, our data indicate that mutations in the MC4-R are not uncommon. Whereas our data support the evidence for dominantly inherited obesity as revealed by the three obese probands with haplo-insufficiency, the functional significance of the missense mutations remains to be determined.

Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN). These candidate genes were evaluated for sequence variation and for linkage and association of this sequence variation to AN in family and case : control data sets. Resequencing of the HTR1D locus and a portion of the OPRD1 locus identified novel SNPs and confirmed existing SNPs. Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls. Linkage analysis of these candidate gene SNPs with 33 microsatellite markers in families including relative pairs concordantly affected with restricting AN (N=37) substantially increased the evidence for linkage of this region to restricting AN to an NPL score of 3.91. Statistically significant genotypic, allelic, and haplotypic association to AN in the case : control design was observed at HTR1D and OPRD1 with effect sizes for individual SNPs of 2.63 (95% CI=1.21-5.75) for HTR1D and 1.61 (95% CI=1.11-2.44) for OPRD1. Using genotype data on parents and AN probands, three SNPs at HTR1D were found to exhibit significant transmission disequilibrium (Po0.05). The combined statistical genetic evidence suggests that HTR1D and OPRD1 or linked genes may be involved in the etiology of AN.

OBJECTIVE:The goal of the present study was to identify covariates and predictors of post-treatment weight reduction. To clarify the impact of the individual factors, we compared 'winners' (losing more than 2 BMI-points in the follow-up period) with 'losers' (gaining more than 2 BMI-points in the same time). DESIGN: In a questionnaire based study, we evaluated the psychological impact on eating behavior, general psychopathology and depressive symptoms at three points in time: three months prior to admission (T0), at the beginning (T1) and at the end of in-patient treatment (T2) as well as 6, 12, and 18 months after treatment (T3 -T5). SUBJECTS: One hundred and thirty eight obese patients (BMI < 30 kg=m 2 ) were recruited to the study. All patients participated in a multimodal in-patient treatment program over a period of 10 weeks. Treatment elements were cognitive behavioral therapy, movement therapy, and nutritional counseling. The aim of treatment was to regulate food intake, to minimize dysfunctional emotional influences on eating behavior, to enhance physical exercise and to treat comorbid psychiatric disorders. Twenty nine patients (13%) of the initial sample dropped out or were excluded during the treatment and post-treatment period. RESULTS: During in-patient treatment eating behavior improved and body weight decreased considerably in all patients. The weight reduction continued slightly in the follow-up period. Moreover, general psychopathology, depressive symptoms and eating behavior improved and remained stable during follow-up. These benefits were closely related to weight reduction. Neither eating behavior, nor eating related cognition nor psychopathology measured at T0 and T1 predicted long term success at T5. 'Winners' as compared to 'losers' at follow-up showed less psychopathology, less depressive symptoms and a less disturbed eating behavior. Already at discharge (T2), winners were less prone to eating triggered by external stimuli and reported fewer feelings of hunger. These differences predicted post-treatment weight reduction (T3 -T5). CONCLUSION: Reported feelings of hunger and the tendency to disinhibited eating behavior measured at discharge were able to predict post-treatment weight reduction in our sample. Patients suffering from a feeling of hunger during in-patient treatment were less likely to show further weight reduction in the follow-up period. Similarly, reduction of 'disinhibition' during treatment is a precondition for post-treatment weight loss.

Compared with a control group (patients on a waiting list) significant and clinically relevant effects were found. At the outcome, there were significant improvements in almost all parameters measured. For evaluation of the long-term effect we succeeded in contacting 312 of 434 former patients. Data were assessed using the same questionnaires that had been employed at the first contact. In all, 271 patients (86%) returned the questionnaires. Data for 244 cases (mean age 63 years; 79 females, 165 males) were complete enough to be used for data analysis. The results of the follow-up were as unexpected as clear: 15 years after conclusion of the treatment, the improvements of the tinnitus parameters and additional symptoms were stable when compared with the end of therapy.

Estrogens are known to have an inhibitory effect on food intake in rodents and primates. Decreased estrogen levels that are found for instance in menopausal woman and in ovarectomized rodents result in body weight gain. Estrogen can act both in the periphery and in the central nervous system via at least two different estrogen receptors (alpha and beta). We systematically screened the coding region and part of the 5' and 3'regions of the estrogen receptor beta gene (ER beta) in 96 extremely obese children and adolescents, 50 patients with anorexia nervosa (AN), 28 patients with bulimia nervosa (BN), and 25 healthy underweight individuals. We detected five different sequence variants in the ER beta: a) A 21 bp deletion (codons 238 to 244) was detected in two obese probands and an underweight individual. b) An 846G-->A transition leading to a nonconservative amino acid substitution (G-250-S) was found in two obese male probands. Both a) and b) were located within the flexible hinge region between DNA and ligand binding domain. c) For a 1082G-->A polymorphism we found suggestive evidence for an association between the more common 1082G-allele and anorexia nervosa (nominal p=0.04). d) One silent mutation (1421T-->C) was found solely in two obese probands. e) A common variant is located in the 3' nontranslated region at position 1730(A-->G). We did not detect association of this polymorphism to any of the analyzed phenotypes. We conclude that the ER beta harbors several different mutations and polymorphisms, none of which can readily be associated with the phenotypes under study.