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Elevated Physical Activity and Low Leptin Levels Co-occur in Patients with Anorexia Nervosa

Departments of Child and Adolescent Psychiatry and Psychotherapy (K.H., B.H.-D.) and Medical Statistics (N.H.), Aachen University, D-52074 Aachen, Germany; German Aerospace Center-Institute of Aerospace Medicine, Space Physiology (C.M., M.H.), D-51170 Cologne, Germany; Roseneck Hospital for Behavioral Medicine (M.F.), D-83209 Prien, Germany; Department of Psychiatry (M.F.), University of Munich, D-80336 Munich, Germany; Clinic of Psychotherapy and Psychosomatics (S.H., W.S.), University of Essen, D-45122 Essen, Germany; Lilly Deutschland GmBH (W.F.B.), D-61350 Bad Homburg, Germany; Childrens Hospital of the University of Giessen (W.F.B.), D-35385 Giessen, Germany; Department of Psychiatry and Psychotherapy (U.S.), University of Lübeck, D-23538 Lübeck, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy (A.W.), University of Würzburg, D-97090 Würzburg, Germany; and Department of Child and Adolescent Psychiatry and Psychotherapy (A.B., H.R., J.H.), University of Marburg, D-35033 Marburg, Germany

Address all correspondence and requests for reprints to: Professor Dr. Johannes Hebebrand, Clinical Research Group, Department of Child and Adolescent Psychiatry, Hans-Sachs-Strasse 6, D-35033 Marburg, Germany. E-mail: Hebebran{at}post.med.uni-marburg.de.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
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 (R² = 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.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
ANOREXIA NERVOSA (AN) is associated with a number of somatic and psychopathological symptoms that result from semistarvation. Prominent somatic symptoms include hypothermia, reduced heart rate, lowered blood pressure, reduced hematopoiesis, and diverse endocrinological alterations (1). Amenorrhea, which is a criterion of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for the diagnosis of this eating disorder in females, frequently sets in after caloric restriction has been initiated (2). These somatic symptoms can be viewed as a meaningful adaptation to a reduced energy intake, because they, in total, serve to decrease the energy requirements of the organism. They account for the fact that patients can survive with daily energy intakes well less than 1000 kcal (3). The psychopathological symptoms prominent in acute AN encompass depression, rigidity, weight phobia, and preoccupation with thoughts related to food and eating (1). Studies in healthy probands subjected to a prolonged energy restriction indicate that some of these symptoms, in particular depressed mood and preoccupation with food and eating, reflect a psychophysiological reaction to semistarvation (4, 5).

Leptin is presumably the major hormone to trigger the adaptation of an organism to food restriction (6, 7). Leptin, which is mainly synthesized in adipocytes, is secreted into the blood stream (8). In humans, serum leptin levels are correlated with the body mass index (BMI; kg/m²) and percentage of body fat (8). Serum leptin levels drop not only as a result of loss of fat mass but also in a more dynamic fashion upon a short-term food restriction, which is not accompanied by substantial weight loss (9, 10, 11). The long form of the leptin receptor is located in the hypothalamus, which is involved in maintenance of energy homeostasis. The short form of the receptor can be found in many tissues including brain, hematopoietic stem cells, bone, kidney, and lung (12, 13). The role of leptin role in the adaptation to semistarvation is based on several findings in animal models: The down-regulation of the hypothalamic-pituitary-gonadal and thyroid axes and the up-regulation of the adrenal axis observed upon food restriction are blunted by application of exogenous leptin (7). Leptin modulates the brain reward circuitry, suggesting that leptin might make complementary contributions to energy balance by reducing food reward while enhancing the value of behaviors incompatible with feeding (14). In line with this behavioral effect, leptin administration has been shown to suppress semistarvation-induced hyperactivity (SIH) both before and after its onset in food-restricted rats (15). This SIH has been viewed as a model for elevated physical activity levels frequently associated with AN (20, 21, 22, 23).

Taken together, these findings indicate that the drop in leptin secretion associated with weight loss induced via a reduced energy intake is a major trigger underlying both somatic and behavioral adaptation to semistarvation. In the following, we use the term "hypoleptinemia" to indicate that a subthreshold leptin secretion has triggered the initiation of the adaptation to semistarvation. With the use of a sensitive RIA, we have previously shown that a serum leptin level of less than 1.85 µg/liter predicts a lifetime history of amenorrhea, and that patients with AN typically have levels below this value (37). Furthermore, the same leptin threshold predicts subnormal serum levels of LH (38, 39).

In this context, it is of obvious interest to assess other somatic and behavioral implications of the lowered leptin secretion associated with acute AN. The first objective of the current study was to exploratorily set diverse somatic and psychopathological items obtained in patients with acute AN into relationship to serum leptin levels as determined upon referral for inpatient treatment. Because motor restlessness, as assessed via a seven-point visual analog scale filled in by the respective therapists, was strongly correlated with leptin levels upon referral in our first study group, we proceeded by testing the hypothesis that elevated physical activity levels in AN patients, as assessed with a standardized semistructured interview, are related to serum leptin levels in the second study group.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
For the first descriptive part of this study, 61 female patients (study group 1) with a DSM-IV (24) diagnosis of AN were ascertained at four inpatient units that specialize in the treatment of adolescent (Marburg and Würzburg) and adult (Essen and Prien) patients, respectively. Eighteen subjects were classified as binge-eating/purging anorectics, and 38 were classified as restricting subtype according to DSM-IV criteria; in 5 patients, no data were available for classification of the subtype. Apart from contraceptives, patients (n = 9) took no medication upon admission. A subsample of these patients have been previously described by Exner et al. (15), who demonstrated that increments in leptin levels during inpatient treatment were associated with drops in patients’ self-ratings of motor restlessness. At two of the participating centers (Marburg and Essen), diverse somatic and self- and expert (the therapist who treated the individual patient)-rated cognitions and behaviors were determined for each patient within the first 3 d after referral for inpatient treatment. Seven-point visual analog scales were used to assess the self- (15) and expert-rated behaviors and cognitions, respectively. Refusal or absence of the patient or absence of the therapist at the time of the scheduled initial assessment via the visual analog scales led to missing data. Ratings and anthropometric variables (see Tables 2 and 3) were obtained on the same day that blood was sampled after an overnight fast. The routine lab evaluations were performed at the respective center; leptin was measured in the laboratory of W.F.B. as described previously (25). In Marburg, body impedance analyses (Data Input 2000S, Frankfurt, Germany) were additionally performed. Patients ascertained in Prien and Würzburg were merely initially blood sampled for determination of the correlation of serum leptin levels to BMI in this large study group.

Serum leptin levels at referral (blood sampling after an overnight fast within the first 3 days upon admission) were measured in Aachen using a commercially available sensitive RIA (Mediagnost, Tübingen, Germany; intra-assay variance, <5%; interassay variance, <7.6%).

The studies were approved by the Ethics Committees of the Universities of Marburg and Aachen, respectively, and patients gave their written informed consent, which was supplemented by the signature of at least one parent in the case of minors.

Characteristics of patients and the serum leptin concentrations of both study groups are shown in Table 1.

As described previously (27), logarithmic (lg10) transformation was performed for leptin levels to avoid an asymmetrical distribution. Kolmogorov-Smirnov test was used to test for normality. Spearman correlation test was used for nonparametric data, and Pearson correlation test was used for parametric variables. Correlation coefficients were calculated between lg10 serum leptin levels and anthropometric variables, blood parameters, and levels of physical activity, respectively. In study group 2, Pearson correlation coefficient was calculated between lg10 serum leptin levels and activity levels only; based on the hypothesis generated in study group 1, significance was defined as P 0.05 as determined in a one-sided test. A logistic regression model with ordinal response was calculated to examine the relationship between lg10 leptin concentrations and physical activity levels adjusted for BMI, for which significance was defined as P 0.05. Data are presented as mean ± SD. Calculations were performed using SPSS software.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Tables 2 and 3 summarize the correlations between lg10 serum leptin levels and somatic variables including blood parameters and psychometric items, respectively, obtained in study group 1. Of the anthropometric variables, only waist circumference was not correlated with lg10 leptin levels. Among all the other somatic and psychological variables considered, only three revealed P values lower than 0.05 uncorrected for the multiple tests. All three pertained to expert ratings: mood (r = 0.42; P = 0.008), appetite (r = 0.352; P = 0.03), and motor restlessness (r = -0.476; P = 0.003). Patients’ self-ratings of mood (r = -0.014; P = 0.934) and appetite (r = -0.164; P = 0.348) were not correlated to lg10 leptin levels, whereas self-ratings of motor restlessness (r = -0.290; P = 0.096) showed a trend in the same direction as for the expert ratings.

The mean sum score of the SIAB-EX item "excessive exercise" of the patients of study group 2 (2.5 ± 1.3) was higher than the mean score (0.9 ± 0.8) of the adult (20.9 ± 3.2 yr) control sample in the SIAB-EX validation study (26). Physical activity levels as assessed with the SIAB-EX were significantly correlated with lg10 leptin levels (r = -0.51; one-sided value of P = 0.006; Fig. 1). The regression model based on the independent variables BMI and leptin levels (lg10) explained 37% (R² = 0.37; P = 0.003) of the variance of physical activity levels. Only lg10 leptin level (P = 0.003) but not BMI (P = 0.205) contributed significantly to the variance of activity levels. Age was not significantly correlated with lg10 leptin levels (r = -0.02; P = 0.93).

View larger version (11K): [in this window] [in a new window]   FIG. 1. Study group 2. Scatterplot of Ig10 serum leptin levels at admission of 27 adolescent patients with AN vs. levels of physical activity of the last 3 months before admission as assessed by the SIAB-EX (26 ).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Because leptin has been shown to stimulate both erythroid and myeloid development (28), is required for normal lymphopoiesis (29), and accounts for the immune dysfunction observed in starvation (30), the correlations between leptin and cell counts of erythrocytes (r = 0.259; nominal P = 0.086) and lymphocytes (r = 0.325; nominal P = 0.061) deserve notice. Further studies appear warranted to assess whether hypoleptinemia accounts for low erythrocyte and lymphocyte counts in acute AN. In addition, it is conceivable that some of the other variables might also be dependent on leptin levels; intraindividual variability of the influence of leptin on the respective variables, e.g. different threshold values, and/or the influence of other factors not considered in the current study might obscure an existing relationship.

In study group 2, we were able to confirm the hypothesis that leptin levels at admission for inpatient treatment predict physical activity levels. The hypothesis had been based on the results obtained for motor restlessness in study group 1. The observed correlation between activity levels and lg10 leptin levels was significant; our regression model revealed that leptin and not BMI underlies the detected relationship. Thus, our study supports a potential link between hypoleptinemia and elevated physical activity levels in patients with AN. This suggested link is in accordance with the study by Exner et al. (15), who on a descriptive basis showed that, during inpatient treatment, increments of leptin levels induced by weight gain are paralleled by drops in patients’ self-ratings of motor restlessness.

The correlation of r = -0.51 between lg10 leptin levels and the level of physical activity detected in our second and independent study group must be viewed in light of the complexity of assessing physical activity; it can be argued that the effect might actually be stronger if objective measurements are employed. Our results are also consistent with studies of SIH in rats, which is considered a biological model of AN. Leptin unequivocally plays a crucial role in mediating hyperactivity in semistarved rats (15); both the induction of SIH and its maintenance can be suppressed by exogenous application of leptin. Studies in other vertebrates do not demonstrate a clear relationship between food restriction and elevated physical activity. For example, Weed et al. (31) demonstrated increments in motor activity in rhesus monkeys due to chronic food restriction (6 yr). In contrast, Kemnitz et al. (32) observed a small but statistically significant reduction in physical activity for monkeys on dietary restriction (1 yr).

Seemingly in contrast to our findings, the spontaneous activity of ob/ob mice as well as Zucker rats is lower compared with age-matched lean controls (16, 17). Furthermore, the treatment of ob/ob mice with leptin not only decreases food intake and body mass but also increases spontaneous activity (18). An increased physical activity, which paralleled weight loss, was observed in a genetically leptin-deficient child during treatment with exogenous leptin (19); Farooqi et al. (19) concluded that this higher level of physical activity was due to the observed improvement in the child’s mobility. A possible explanation for this discrepancy is that the reaction of the organism to leptin differs between individuals who were never exposed to leptin and healthy individuals in whom decreasing leptin levels mediate the adaptation to semistarvation. Also, we cannot exclude the possibility that, in chronically ill AN patients, an adaptation to the low leptin secretion occurs in that activity levels are no longer influenced by leptin; in this context, it is important to point out that all of the patients in study group 2 were adolescents.

Elevated activity levels have been observed unsystematically in humans suffering from hunger (23). In contrast, the following descriptions of physical activity of the males participating in the Minnesota Semi-Starvation Study (6) indicate a reduced level of physical activity; however, the observations are not totally congruent and potentially reflect interindividual differences in response to semistarvation: "The attitude of the men to physical exertion was ambivalent. It made them tired and as a rule was avoided. On the other hand, occasionally some men exercised deliberately. Thus certain subjects attempted to lose weight by driving themselves through periods of excessive expenditure of energy with the object of either obtaining increased bread rations (when weight loss exceeded the prescribed rate) or avoiding reduction in rations (when weight loss lagged).... subjects moved slowly and cautiously.... curtailment of spontaneous activity.... the men rated themselves as... restless, unable to concentrate, and markedly nervous." Gender, genetic factors, diet, and both the degree and duration of food restriction might explain some of the discrepant findings pertaining to activity levels upon caloric restriction. It deserves to be pointed out that a paradoxical liveliness induced by food restriction might actually mark the gateway into AN in individuals who are thus predisposed (33).

In AN physical activity has not received much attention from clinical researchers, although elevated physical activity is present in 30–80% of AN patients (23, 34). It is commonly assumed that excessive physical activity is mainly performed by patients to control weight via both increased energy expenditure and appetite suppression. Thus, excessive physical activity is viewed as a consequence of cognitive processing (weight preoccupation). Accordingly, treatments aimed at weight restoration use operant conditioning to prevent excessive physical activity. Nevertheless, patients clearly do exercise covertly. Furthermore, excessive exercise has been viewed as an affect regulation strategy among AN patients (35, 36). Subjective reports of patients’ experiences of elevated physical activity levels sometimes have an ego-dystonic and compulsive quality, indicating that exercise might not be under cognitive control of a patient. However, particularly at the beginning of weight loss, many patients retrospectively clearly attribute their high activity levels to their desire to lose weight. Elevated activity levels in patients could have multiple underlying mechanisms whose relative contribution might differ according to the stage of the disorder.

The following limitations apply to our study. First, motor restlessness as assessed in study group 1 is not identical with physical activity as assessed in study group 2. In the large study group 1, the respective therapists had rated motor restlessness, and in study group 2, a single trained interviewer rated all of the patients using the SIAB-EX module for assessment of physical activity, which allows the differentiation of five activity levels. We are not aware of any standardized instrument to specifically rate motor restlessness. We assume that the dimension assessed via levels of physical activity as delineated in the SIAB-EX (see Patients and Methods) strongly overlaps with the dimension that we originally circumscribed with motor restlessness. Nevertheless, the interview instructions indicate that inner restlessness and nervousness and problems in sitting still are not to be considered for the rating. Therefore, further studies with more objective measurements of different qualities of physical activity are definitely required to substantiate our finding. Second, all of our patients were acutely ill; thus the relationship might apply only to a similarly ascertained group. This would intuitively make sense if leptin levels only influence activity levels when they drop into the semistarvation range and thus beyond a critical and as-yet-undetermined threshold range. As discussed above, the relationship might not apply any longer in patients with a long duration of their eating disorder. Third, in our exploratory analyses, we did not adjust for BMI. However, in the semistarved state, the correlation between BMI and lg10 leptin levels is lower than in healthy individuals; based on our data obtained for a subgroup of study group 1, a plausible explanation is that variation in percent fat mass is greater at low BMIs. Furthermore, it is not known whether the adjustment of leptin levels for BMI is appropriate at all. On the one hand, absolute leptin levels may be relevant for central leptin actions. On the other hand, leptin levels adjusted for BMI may reflect the physiological situation in AN patients more accurately. Fourth, the absence of measurements of body fat in study group 2 clearly reflect a limitation of our study. It seems possible that increased exercise levels could be associated with a relative decrease in percentage of body fat, thus contributing to the significant inverse correlation between physical activity and serum leptin observed in study 2. Therefore, further studies should include the assessment of body composition to clarify whether the relation of leptin levels and physical activity is independent not only of BMI but also of the percentage of body fat.

In conclusion, our results warrant a critical consideration of the mechanisms underlying elevated activity levels in patients with AN. It clearly appears possible that biological factors and, in particular, hypoleptinemia contribute to this phenomenon. The potential implications for our understanding of the symptoms in acute AN need to be addressed, including those for therapy. We have previously suggested (15) that acutely ill patients could potentially benefit from leptin administration via a reduction of their excessive physical activity.

	Acknowledgments

 
We thank the patients for their participation in this study. The contribution of Tillmann Görg (Institute of Medical Biometry and Epidemiology of the Philipps University Marburg) is gratefully acknowledged.

	Footnotes

 
This work was supported by the Christina Barz-Stiftung (Essen, Germany), the START program of the Technical University of Aachen (Aachen, Germany), Deutsche Forschungsgemeinschaft (DFG RE 471/11-2), and Bundesministerium für Bildung und Forschung (NeuroNet Marburg, German National Genome Research Network; 01 GS 0168 and 01 GS 0118).

Abbreviations: AN, Anorexia nervosa; BMI, body mass index; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; SIAB-EX, Structured Inventory for Anorexic and Bulimic Syndromes; SIH, semistarvation-induced hyperactivity.

Received April 2, 2003.

Accepted July 18, 2003.

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