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Objective: Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto(-/-) mice are lean and Fto(+/-) mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.Research Design and Methods: We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.Results: We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.Conclusions: Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study with 31 obese binge eaters (body mass index [BMI] 39.5+/-8.6 kg/m(2) [SD]) was designed to assess whether diet counseling with psychological support and imipramine or placebo has an effect on the frequency of binge eating, body weight, and depression during an 8-week treatment phase. This was followed by an open medication-free phase of 6 months of continuous diet counseling with psychological support. METHODS: Randomized double-blind placebo-controlled study of 8 weeks followed by an open phase of 6 months. Patients were evaluated in medical visits by a semistructured videotaped interview, psychometric questionnaires, and hematochemical parameters. RESULTS: From Week 0 to 8, a significant reduction in binge frequency occurred in both treatment conditions (7.1+/-4.1 to 2.8+/-3.0 binges per week [imipramine] vs. 7.1+/-4.1 to 5.4+/-5.1 [placebo], p<.01). Patients on imipramine lost -2.2+/-1.8 kg compared to placebo-treated subjects (+0.2+/-3.3 kg, p<.001). On follow-up, only the patients initially treated with imipramine continued to lose weight (-5.1+/-2.8 kg [imipramine] vs. 2.2+/-6.8 kg [placebo], p<.001 [differences to Week 0]). While both treatment conditions were associated with significant improvements on a rater's measure of depressive symptoms (Hamilton Depression Scale) at Week 8, only the patients treated with imipramine still showed a significant improvement at Week 32. Scores on the Self Depression Rating Scale did not show a group difference but a significant reduction at Weeks 8 and 32, compared to baseline. DISCUSSION: These results suggest that adding low-dose imipramine to diet counseling with psychological support helps patients losing weight even for at least 6 months off medication. The effect might include a psychological priming of weight loss during the double-blind phase that continues at least for half a year after stopping the drug. Copyright 1999 by John Wiley & Sons, Inc. [ABSTRACT FROM AUTHOR]

Fat distribution was assessed by computed tomography in normal volunteers (n = 42), patients on long-term dialysis (n = 18), and patients on glucocorticoids [renal transplant patients (n = 49), other diseases (n = 17)]. Patients on glucocorticoids had higher mediastinal (deep) and identical or increased posterior cervical, buccal, and midthigh (superficial) fat areas when compared with normal subjects. The pattern of fat distribution in dialysis patients mimicked the distribution observed in patients taking glucocorticoids. Healthy females had higher ratios of superficial to deep fat than healthy male subjects on prednisone or on dialysis lost this sex-associated difference in fat distribution. Since patients on prednisone exhibit increased or normal thigh fat depots in the presence of increased mediastinal fat, the current concept that glucocorticoids induce redistribution of body fat from peripheral to central fat compartments has to be revised. Furthermore, disease states and/or glucocorticoids abrogate sex-associated differences in body fat distribution. [ABSTRACT FROM AUTHOR]