Low leptin levels are an endocrinological hallmark of acute anorexia nervosa (AN); a subthreshold leptin secretion in adipocytes as a consequence of a reduced energy intake is presumed to be the major trigger of the adaptation of an organism to semistarvation. The aim of the current study is to define symptoms of AN that are potentially linked to low leptin levels. For this purpose, quantitative somatic and psychopathological variables were obtained in 61 inpatients with acute AN (study group 1) upon referral for inpatient treatment, and they were concomitantly blood sampled to allow determination of serum leptin levels. Correlations between these variables and logarithmic transformed (lg10) leptin levels were descriptively assessed. Apart from the well-known correlations between leptin levels and anthropometric measurements, the strongest correlation was observed between lg10 serum leptin levels and expert ratings of motor restlessness (r = -0.476; nominal P = 0.003) upon use of visual analog scales. We thus generated the hypothesis that physical activity levels in AN patients are related to serum leptin levels. This hypothesis was tested in an independent study group of 27 adolescent inpatients (study group 2) who were also assessed upon referral. Physical activity levels, which, in this study group, were assessed with the activity module of the expert rating form of the Structured Inventory for Anorexic and Bulimic Syndromes, were significantly correlated with lg10 leptin levels (r = -0.51; one-sided P = 0.006). A regression model based on the independent variables body mass index and lg10 leptin levels explained 37% of the variance of physical activity (R(2) = 0.37; P = 0.003); only the lg10 leptin levels contributed significantly to the variance (P = 0.003). Our results suggest that, similar to semistarvation-induced hyperactivity in rats, hypoleptinemia in patients with AN may be one important factor underlying the excessive physical activity.

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 1.85 g L −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 1.85 g L −1 was supported for LH only.The first hint of leptin's important role in fertility became evident upon reproductive rescue of female ob/ob mice treated with exogenous leptin. 1 Young wild-type mice treated with leptin reproduce earlier than non-treated animals. 2 Leptin also blunts the response of the reproductive axis to starvation; both levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) do not drop to levels characteristic of semi-starvation, if food-deprived mice are injected with leptin. 3 In in vitro studies leptin produced a dose-related increase in FSH and LH in hemi-anterior pituitaries. Low doses of leptin produced increases in secretion of LH-releasing hormone (LH-RH) upon incubation of median eminence-arcuate nuclear explants from male rats. 4 In ovariectomized female rats plasma LH, but not FSH levels, increased after intraventricular application of leptin. 4 Leptin acts both at the hypothalamic and pituitary level to stimulate nitric oxide release which in turn mediates LH-RH or LH release, respectively. 5 In humans leptin might be the mediator between the adipose tissue and the central events underlying menarche and maintenance of reproductive function. Indeed, a leptin threshold level for initiation of reproductive ability in women has been suggested. 6 In girls leptin levels increase during puberty, 7,8 leptin increments are followed by increments of FSH and later by LH and estradiol. 8 Leptin possibly regulates the minute-to-minute oscillations in the levels of LH and estradiol. 9 Mutations in both the leptin gene and the leptin receptor gene are associated with primary amenorrhea in females. 10,11 In postmenarcheal females, seco...

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 index 4 (BMI: kg m −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.

Amenorrhea in female patients with anorexia nervosa is associated with low leptin secretion, thus suggesting a causal link. In an attempt to address the hypothesis that leptin also influences the hypothalamo-pituitary-gonadal function in males, we studied three male patients with acute anorexia nervosa longitudinally. Serum levels of leptin, LH, FSH, testosterone, and SHBG were measured on a biweekly basis during weight gain. Leptin levels at low body mass index values were below the 5th percentile. During weight gain, leptin levels reached or surpassed the 95th percentile. The temporal dynamics of body mass index and fat mass were closely related to those of leptin concentrations in serum. Leptin increments were paralleled by increments of gonadotropins, testosterone, and the free androgen index (FAI). In each of the patients, serum concentrations of leptin were positively correlated with those of testosterone (P = 0.0001, P = 0.01, P = 0.07, respectively) and FAI (P = 0.0001, P = 0.0001, P = 0.09, respectively). In addition, in the combined data set of all patients changes of leptin over time were positively correlated with changes in LH (P = 0.01), FSH (P = 0.0001), testosterone (P = 0.002), and FAI (P = 0.002). In conclusion, these data suggest that leptin might also play an important role in the regulation of the hypothalamo-pituitary-gonadal axis and fertility in underweight males as has previously been shown in underweight females.

Underweight is a key symptom in anorexia nervosa. In this review we summarize recent findings pertaining to weight regulation in this eating disorder. The observation that a body mass index below 13 kg/m2 upon admission for inpatient treatment is associated with a high mortality rate and chronic persistence of underweight is of obvious clinical relevance. A lowered leptin secretion, which results from the weight loss, is presumably of major importance for the development of amenorrhea. We discuss findings pertaining to a reduced body weight in other psychiatric disorders during adolescence in the light of Kretschmer's findings related to body frame and psychopathology.