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The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 12
Printed in U.S.A.
Decreased Serum Leptin in Bulimia Nervosa*
DAVID C. JIMERSON, CHRISTOS MANTZOROS, BARBARA E. WOLFE,
ERAN D. METZGER
AND
Department of Psychiatry (D.C.J., B.E.W., E.D.M.), Division of Endocrinology, and Department of
Medicine (C.M.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston,
Massachusetts 02215
ABSTRACT
The eating disorder bulimia nervosa has been associated with
impaired satiety, decreased resting metabolic rate, and abnormal
neuroendocrine regulation. Preclinical studies suggest that such alterations could be associated with impaired leptin function. Thus, the
goal of this study was to assess whether leptin function is decreased
in bulimia nervosa. Serum leptin levels measured in women with
bulimia nervosa (n ⫽ 18) and in women who had maintained stable
recovery from bulimia nervosa (n ⫽ 15) were compared with values
in healthy female controls (n ⫽ 20). Subjects were studied during the
follicular phase of their menstrual cycle after an overnight fast and
T
HE EATING DISORDER bulimia nervosa is characterized by recurrent binge eating, compensatory behaviors to avoid weight gain, and related behavioral and physiological symptoms. Studies of eating behavior in bulimia
nervosa have demonstrated impaired postingestive satiety
(1), possibly associated with diminished responsiveness in
satiety-related pathways involving serotonin or other hypothalamic neurotransmitters (2, 3).
Leptin, the protein product of the ob gene, is thought to
influence weight regulation by acting in the central nervous
system to decrease food intake, as recently reviewed (4 – 6),
although there are limited data on the magnitude of this
effect in primates and humans (7, 8). In rodents, leptin administration decreases meal size (9, 10), suggesting that decreased leptin function could contribute to diminished satiety responses and large binge meals in bulimia nervosa.
Additionally, alteration in leptin function affects other neuroendocrine systems, as illustrated by the fact that decreased
blood thyroid hormone concentrations may be associated
with a fall in leptin levels (4). Thus, as noted in Discussion,
decreased leptin function could contribute to abnormalities
in neuroendocrine regulation associated with bulimia
nervosa.
To test the hypothesis that abnormal regulation of leptin
Received January 13, 2000. Revision received August 15, 2000. Accepted September 9, 2000.
Address all correspondence and requests for reprints to: Dr. David C.
Jimerson, Department of Psychiatry, GZ-718, Beth Israel Deaconess
Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215.
E-mail: [email protected].
* This work was supported in part by USPHS Grants R01-MH-45466
(to D.C.J.) and K07-MH-00965 (to B.E.W.) from the NIMH and RR-01032
(to the General Clinical Research Center at Beth Israel Deaconess Medical Center) from the National Center for Research Resources, NIH.
Presented in part at the Annual Meeting of the American Psychiatric
Association, Washington, D.C., May 18, 1999.
bed rest. Baseline serum samples were analyzed for leptin concentration by RIA. Subject groups were matched for age and body weight.
Analysis of covariance, adjusting for percent body fat, demonstrated
abnormally low serum leptin levels in the bulimia nervosa group (P ⫽
0.02), with a trend toward an inverse correlation between frequency
of binge episodes and serum leptin concentration (P ⬍ 0.1). Additionally, the remitted patient group demonstrated abnormally low leptin
values (P ⫽ 0.01). These results are consistent with the hypothesis
that decreased leptin function may be associated with alterations in
eating patterns, metabolic rate, and neuroendocrine regulation in
bulimia nervosa. (J Clin Endocrinol Metab 85: 4511– 4514, 2000)
may be associated with abnormalities in eating patterns and
neuroendocrine hormone levels in bulimia nervosa, this
study compared serum leptin concentrations in carefully
characterized out-patients meeting diagnostic criteria for bulimia nervosa to results for weight-matched healthy control
subjects. Studies were also conducted in individuals who had
recovered from bulimia nervosa to assess whether postulated abnormalities in leptin regulation persist after symptom remission.
Subjects and Methods
Subjects
Subjects were recruited from university-affiliated eating disorder
programs and from the community for psychobiological studies including serotonin-related neuroendocrine and behavioral assessments (11,
12). Diagnostic evaluations were based on a modified version of the
Schedule for Affective Disorders and Schizophrenia-Life Version (13).
The patient group included women who met DSM-III-R criteria for
bulimia nervosa (14), with the additional criteria of binge eating and
purging, on the average, at least three times per week over the preceding
6 months. The remitted group included women who had previously met
these modified criteria but had been abstinent from binge eating and
purging and had experienced normal menstrual cycles for 3 or more
months before study.
The patient and remitted groups had been free of major depression,
alcoholism, and substance abuse disorders for at least 6 months and free
of psychotropic medications for at least 8 weeks before study. The
control group included women with no history of an eating disorder or
other major psychiatric disorder. Subjects were at normal weight [body
mass index (BMI), 18 –26 kg/m2], had not been pregnant or used oral
contraceptives within the preceding 6 months, and were in good medical
health as assessed by medical history, physical examination, and baseline laboratory studies, including pregnancy and toxicology screening
tests. Subjects abstained from alcoholic beverages for at least 1 week
before study. The study protocol was approved by the institution’s
human studies review board, and all subjects gave written informed
consent before study participation.
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Procedures
TABLE 1. Descriptive characteristics of subject groups
Subjects were admitted to the Clinical Research Center for two neuroendocrine study days, scheduled during the follicular phase of the
menstrual cycle (with the exception of one amenorrheic bulimic subject).
After an overnight fast and bed rest on the in-patient unit, on the first
in-patient day two baseline blood samples for leptin determination were
obtained through an iv catheter at approximately 0840 and 0855 h.
Additional baseline hormone measurements included serum PRL and
cortisol as well as estradiol, progesterone, T3, free T4, and TSH obtained
on the second study day 24 h later (72 h later for two subjects). Percent
body fat was calculated based on skinfold measurements (15, 16).
Laboratory methods
Serum samples were stored at ⫺70 C until analyzed by immunoassay,
as previously described (12, 17).
Data analysis
Group data are presented as the mean ⫾ sd (mean ⫾ sem in Fig. 1).
Initial review of hormone data revealed that 1 participant in each subject
group had a baseline estradiol level more than 3 sd greater than the
group mean. To avoid potentially confounding outlier effects of elevated
estradiol on other neuroendocrine measures, results for these 3 individuals were excluded from subsequent data analysis. Descriptive characteristics for the remaining 18 patients with bulimia nervosa, 15 remitted individuals, and 20 healthy controls were compared by ANOVA
or by Kruskal-Wallis test for variables not normally distributed. The two
baseline leptin determinations for each subject were averaged to help
minimize sampling effects associated with pulsatile variations (18). Serum leptin concentrations were compared across study groups by analysis of covariance, adjusting for percent body fat. Statistical significance
(two-sided) for separate preplanned comparisons of the bulimic and
remitted groups with the control group was set at P ⬍ 0.025. Pearson
correlation coefficients were used to assess the relationship between
serum leptin and clinical measures. The relationship between serum
leptin and other baseline hormone values was assessed within each
subject group by partial correlation, adjusting for percent body fat, with
the significance level set at P ⬍ 0.01 to adjust for multiple tests.
Results
The subject groups were not significantly different in age
or weight-related measures (Table 1). For the bulimia nervosa group, the frequency of binge eating episodes was 6.0 ⫾
2.7/week, and the frequency of self-induced vomiting was
6.2 ⫾ 3.3 episodes/week. For the remitted group, the duration of remission was 43 ⫾ 29 months. Serum leptin was
significantly correlated with percent body fat in the bulimic
FIG. 1. Comparison of baseline serum leptin concentrations across
study groups (mean ⫾ SEM), adjusted for percent body fat. Serum
leptin was significantly lower in patients with bulimia nervosa (BN;
n ⫽ 18) than in controls (n ⫽ 20; *, P ⫽ 0.02). Similarly, serum leptin
levels in individuals recovered from bulimia nervosa (BN-R; n ⫽ 15)
were significantly lower than the control values (**, P ⫽ 0.01).
Age
Body mass
index
Body
fat (%)
BN
(n ⫽ 18)
Remitted BN
(n ⫽ 15)
Controls
(n ⫽ 20)
Statistical
significance
23.7 ⫾ 3.9
21.9 ⫾ 2.2
25.5 ⫾ 4.5
22.1 ⫾ 1.6
22.8 ⫾ 3.4
21.7 ⫾ 2.0
␹2⫽3.92; P⫽NS
F⫽0.30; P⫽NS
26.6 ⫾ 5.8
28.5 ⫾ 3.8
27.8 ⫾ 5.0
F⫽0.63; P⫽NS
BN, Bulimia nervosa.
group (r ⫽ 0.707; P ⫽ 0.001), in the remitted group (r ⫽ 0.722;
P ⫽ 0.002), and in the controls (r ⫽ 0.615; P ⫽ 0.004).
Comparison of serum leptin concentrations across subject
groups by analysis of covariance yielded a significant main
effect for diagnostic group (F ⫽ 4.40; P ⫽ 0.018), as well as
for the percent body fat covariate term (F ⫽ 37.1; P ⬍ 0.0001).
The serum leptin concentration in the bulimic and remitted
groups was significantly lower than that in controls (Fig. 1).
In the bulimic patient group, there was a trend toward a
correlation between serum leptin concentration and frequency of binge eating (r ⫽ ⫺0.40; P ⫽ 0.098); leptin was not
significantly correlated with the frequency of self-induced
vomiting (r ⫽ ⫺0.17). For the remitted group, the serum
leptin concentration was not significantly correlated with the
duration of remission.
The serum leptin concentration was not significantly correlated with other baseline hormone levels or with age within
any of the subject groups. As described previously, serum
PRL levels were low in the bulimia nervosa group (P ⫽
0.004), and free T4 levels were low in both the bulimic (P ⫽
0.0004) and remitted (P ⫽ 0.002) patient groups compared
with the control values (12). Reanalysis of leptin values including the three individuals with elevated estradiol levels
demonstrated group differences similar to the findings reported above.
Discussion
This study found that nonhospitalized, normal weight
women with bulimia nervosa had significantly decreased
serum leptin levels compared with age- and weight-matched
healthy controls. The trend toward an inverse correlation
between serum leptin levels and frequency of binge episodes
is consistent with the hypothesis that impaired hypothalamic
leptin function contributes to abnormal eating patterns, possibly involving blunted satiety responses. This effect could
involve an interaction with serotonergic satiety pathways
(19). Based on preclinical findings (4), decreased leptin function may contribute to low thyroid hormone levels in bulimia
nervosa (12, 20 –22) as well as to abnormalities in hypothalamic-pituitary-gonadal axis regulation (23–25). These relationships could be further clarified through studies of physiological responses to leptin administration in this patient
group.
The results of this study are consistent with other recent
reports indicating that plasma leptin concentrations in patients with current symptoms of bulimia nervosa were significantly lower than those in healthy controls (26, 27). In
contrast to these results, a previous investigation found that
the serum leptin concentration was not significantly different
in women with bulimia nervosa and healthy controls
DECREASED SERUM LEPTIN IN BULIMIA NERVOSA
matched for BMI (28). In the latter report, however, it is
unclear whether subjects were studied after an overnight
fast, whether subject groups were matched for percent body
fat, and whether patients were studied during a phase of
stable body weight. In another report, serum leptin levels
obtained after an overnight fast in patients with bulimia were
similar to control values, although the extent to which these
groups were matched for BMI or percent body fat was not
indicated (29).
A potential limitation regarding the study findings in both
the symptomatic and recovered eating disorder patients relates to the fact that the serum leptin concentration is sensitive to short-term changes in food intake and to changes
body weight (30 –32). Thus, in a mixed sample of patients
with anorexia nervosa and bulimia nervosa, the plasma leptin concentration was significantly correlated with estimated
caloric intake over the 48-h before study as well as with body
fat mass (33), although plasma leptin levels were not immediately affected by binge eating/purging episodes in a bulimic case report (34). In anorexia nervosa, leptin values are
correlated with BMI, with preliminary evidence for an elevated ratio of cerebrospinal fluid to serum leptin concentrations (17, 35–37).
An additional finding in this study was that serum leptin
levels in women who had recovered from bulimia nervosa
were significantly lower than control values. Thus, decreased
leptin values in symptomatic bulimic patients may reflect a
stable biological trait. Given that patients recovered from
bulimia nervosa appear to have abnormalities in leptin regulation, future laboratory studies to assess whether there are
persistent abnormalities in meal patterns and satiety responses in this subject group would be of interest.
In contrast to the results presented here, a recent study did
not find a significant difference in leptin levels between remitted bulimic patients and controls (38). In this latter study,
however, the recovered individuals were at a significantly
higher BMI than the controls, and data were not available on
percent body fat, which may be a better predictor than BMI
of leptin levels in eating disorder patients (39). Although in
the current study the minimum time for abstinence from
binge eating and purging was briefer than in the previous
report (38), correlational analysis did not show a relationship
between serum leptin concentrations and duration of symptom remission.
Although the resting metabolic rate was not measured in
this study, the findings are consistent with the possibility that
decreased leptin function contributes to abnormally low caloric requirements for maintaining stable weight (40) and
abnormally decreased resting metabolic rate in bulimia nervosa (21, 41). If decreased leptin function were to predate the
onset of bulimia nervosa, it could contribute to the increased
efficiency in energy utilization and unwanted weight gain
(42), prompting the recurrent dieting that commonly precedes the onset of the disorder (43, 44).
Further research is needed to identify factors contributing
to altered serum leptin levels in bulimia nervosa. A familial
tendency toward obesity has been reported in bulimia nervosa (45), although this does not appear to be associated with
leptin gene mutations (46). Sustained weight loss has been
shown to result in a persistent decrease in serum leptin
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concentrations (47, 48). Thus, one contributing factor to low
leptin levels in bulimia nervosa could be a tendency for
patients to maintain their weight below a physiologically
natural (or set-point) weight. A limitation of the current
study is the absence of detailed information on weight stability and nutritional intake (including caloric loss through
self-induced vomiting for the bulimia nervosa patient group)
during the days preceding the subjects’ admission to the
clinical research center. Further studies including these data
as well as measurements of metabolic rate would be helpful
in clarifying whether a net reduction in caloric intake contributes to the decreased serum leptin levels observed in the
patient groups.
In summary, this study found that patients with bulimia
nervosa as well as individuals who had recovered from bulimia nervosa had significantly lower serum leptin levels
than healthy controls matched for BMI and percent body fat.
The results are consistent with the hypothesis that decreased
leptin function contributes to impaired postingestive satiety,
neuroendocrine abnormalities, and abnormally low resting
metabolic rate in bulimia nervosa.
Acknowledgments
We gratefully acknowledge the assistance of the nursing and research
nutrition staffs of the General Clinical Research Center at Beth Israel
Deaconess Medical Center.
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