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Clinical Studies |
Division of Endocrinology, Department of Medicine (C.M., J.S.F.), and the Department of Psychiatry (D.C.J.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; the Department of Psychiatry, University of Texas Medical School (M.D.L.), Houston, Texas 77025; and the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina (T.D.B.), Charleston, South Carolina 29425
Address all correspondence and requests for reprints to: Dr. David C. Jimerson, Department of Psychiatry, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. ; or to Dr. Jeffrey S. Flier, Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. Email: jflier{at}bidmc.harvard.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Administration of small amounts of leptin into the cerebral ventricles decreases food intake in rodents, indicating that leptin acts directly in the central nervous system (CNS) (4, 14). As the long form of the leptin receptor messenger ribonucleic acid is expressed in the hypothalamus (15), and leptin has direct effects on isolated hypothalamic tissue (16), it is likely that the initial step in leptin action occurs at hypothalamic leptin receptors.
It is not yet known whether leptin reaches its sites of action in the CNS by transport across the blood-brain barrier, by direct transport from blood to cerebrospinal fluid (CSF), or by diffusion to sites (e.g. in the hypothalamus) functionally outside the blood-brain barrier. Binding sites have been demonstrated for leptin in the choroid plexus as well as the leptomeninges (15, 17, 18), complementing other evidence for a saturable transport system for leptin into the brain (19).
Measurement of the leptin concentration in the CSF and its relationship to the plasma leptin concentration may provide an important research probe for investigation of disorders of body weight regulation in humans. Recent reports have demonstrated a significant positive correlation between CSF and plasma leptin levels in individuals ranging from normal weight to obese (20, 21). In overweight individuals, there was evidence for a decrease in the ratio of CSF to plasma leptin, suggesting that saturation of the leptin transporter at elevated plasma leptin levels could contribute to leptin resistance in human obesity (20, 21).
The present investigation evaluated the relationship between CSF and plasma leptin concentrations in a combined group of healthy volunteers at normal weight and in low weight patients with anorexia nervosa. Recent reports indicate that plasma leptin concentrations are decreased in anorexia nervosa (22, 23). This study evaluated whether levels of leptin in the CNS, as reflected in CSF leptin concentrations and in the CSF to plasma leptin ratio, are abnormal in patients with anorexia nervosa, and whether such levels are likely to contribute to the onset or maintenance of weight loss characteristic of this disorder. Additionally, given the role of CNS serotonin in postingestive satiety (24), the relationship between CSF concentrations of leptin and the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) was assessed.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The control group included 15 healthy, normal weight women (age, 25 ± 5 yr). All were free of current or past major psychiatric illness, as assessed by standardized interview (25). The patient group included 11 women (age, 24 ± 6 yr) who met criteria for anorexia nervosa based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (26). Patients were medically stable and had no other concurrent medical illness. Subjects were medication free for a minimum of 3 weeks before the study. Before study participation, all subjects gave written informed consent, as approved by the institutional review board.
Study procedures
After a prescreening assessment, healthy volunteers were admitted overnight to a clinical research unit at the Laboratory of Clinical Science, Intramural Research Program, NIMH. Patients were admitted to the same clinical research unit for a combined treatment and longitudinal studies program. After postadmission psychiatric and medical assessments, patients began a 3-week behavioral and nutritional stabilization program. They consumed a diet of 800-1200 Cal/day, designed to maintain their admission body weight. During this low weight phase, patients were introduced to the behaviorally oriented treatment program. The first set of plasma and CSF samples was obtained at the end of the low weight stabilization phase.
During the supervised weight restoration phase of the treatment
program, patients’ dietary intake was progressively increased to
achieve weight gain at a rate of approximately 1.5 kg/week. The second
study phase occurred an average of 81 days after the initial studies,
when patients were approaching their goal weight (approximately 85% of
age- and height-adjusted expected body weight). After reaching their
goal weight, patients participated in the third phase of the treatment
program, which focused on weight stabilization at the goal weight. The
third study phase occurred an average of 32 days after the goal weight
study phase, approximately 3 weeks after patients had achieved their
goal weight. As shown in Table 1
, body mass index (BMI)
had increased substantially by the time of the weight gain study phase
and showed a small significant further increase at the goal weight
phase. Body composition was assessed by anthropometry in seven of the
anorexic patients during the three study phases and in six of the
controls, as previously described (27).
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Laboratory methods
RIA for leptin was performed with components obtained from Linco
Research (Indianapolis, IN). For measurement of plasma leptin,
recombinant human leptin or 50 µL test plasma, in duplicate, were
incubated for 24 h at 4 C with phosphate-buffered saline
containing 0.1% Triton X-100, a 1:2000 dilution of antileptin
antiserum, and 125I-labeled leptin (
15,000 cpm).
Antibody-bound leptin was precipitated by the addition of 500 µL
precipitating reagent. Tubes were centrifuged for 45 min at 2,500 rpm,
after which supernates were decanted, and pellets were counted in a
-counter. For the standard plasma leptin assay, the limit of
detection was 0.5 ng/mL, and the within-assay coefficient of variation
was 4.4% for low levels (2.9 ng/mL) and 5.7% for high levels (14.1
ng/mL). Interassay variations were 6.9% and 9.0%, respectively. All
assays were run twice in duplicate, and results of the two assays were
similar.
The RIA for CSF samples was performed as described above, except that CSF samples (200 µL) were concentrated to a final volume of 50 µL using a Savant lyophilizer (Farmingdale, NY), and the CSF concentrate and antileptin antiserum were incubated at 4 C for 24 h before the addition of tracer leptin. The sensitivity of this modified RIA was 38 pg/mL. CSF concentrations of 5-HIAA were measured by high pressure liquid chromatography (28).
Statistical methods
Statistical analyses were performed using SPSS software (29).
Two-sided significance levels are reported, with statistical
significance set at 
less than 0.05. Group values for outcome
measures are reported as the mean ± SD. Variables not
normally distributed were log transformed and retested for normality
before analysis by parametric methods. Data on body weight and leptin
concentrations in CSF and plasma obtained at the three study phases for
the patient group were compared to control values by t test,
with significance adjusted for multiple comparisons using Dunnett’s
t test. For the anorexic patients, change in outcome
measures from the low weight baseline assessment to subsequent study
phases was assessed by paired t test with Bonferroni
correction for multiple comparisons. Relationships among CSF leptin,
plasma leptin, and body weight were assessed by Pearson correlation
coefficient or, where indicated, by Spearman rank order
correlation.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Comparative data for body weight measurements in the 15 healthy
controls and 11 patients with anorexia nervosa are summarized in Table 1
. In the controls, the mean CSF leptin concentration was 160 ±
58 pg/mL. There was a robust positive correlation between the CSF
leptin concentration and BMI (r = 0.66; df = 13;
P < 0.01; Fig. 1A). In contrast, across
the relatively narrow weight range represented in these subjects, there
was only a weak positive association between plasma leptin levels and
BMI (r = 0.39; df = 13; P = 0.15).
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). The linear relationship shown
in Fig. 1B had a relatively shallow slope, indicating that changes in
CSF leptin levels were likely to be attenuated compared to alterations
in plasma values. Leptin in anorexia nervosa
Compared to controls, low weight patients with anorexia nervosa
had significantly diminished concentrations of leptin in CSF
(t = 3.97; df = 24; P < 0.0005,
by Dunnett’s t test; Fig. 2A). Compared to the measurements
obtained at low weight, CSF leptin values for these patients studied
longitudinally were significantly higher during the active weight gain
phase (t = 5.70; df = 10; P <
0.001) and during the goal weight maintenance phase (t
= 5.07; df = 10; P < 0.005, by paired
t tests with Bonferroni adjustment; Fig. 2A).
For the combined patient and control groups, the CSF leptin
concentration was significantly correlated with BMI (
= 0.73;
df = 24; P < 0.0001), although this relationship
did not reach significance for the anorexic patients evaluated alone at
the three study phases.
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).
There were significant increases in plasma leptin, compared to low
weight values, when the patients were restudied during weight gain
(t = 5.08; df = 10; P < 0.005)
and at goal weight (t = 5.34; df = 10;
P < 0.001, by paired t tests with
Bonferroni adjustment). Plasma leptin values showed a significant
correlation with BMI in the combined subject group ( = 0.83; df
= 24; P < 0.0001), but not in the anorexic patients
assessed separately.
In anorexic patients studied longitudinally, CSF leptin concentrations
reached normal values before full restoration of body weight, as
reflected in the BMI (Fig. 3A). Thus, to the extent that
CSF leptin acts as a CNS signal regarding body weight, this signal
appeared to be prematurely normalized as patients gained weight, as
assessed by BMI. It was of interest that CSF leptin values for the
weight gain and goal weight phases appeared to be appropriately
calibrated when plotted against percent body fat for the seven patients
in whom longitudinal anthropometric measurements were available (Fig. 3B). This finding reflects the fact that during weight restoration, the
anorexic patients experienced a relatively rapid increase in body fat
content relative to lean body mass (27).
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Across the wide range of values for the combined samples from controls and longitudinally studied anorexic patients, there was a significant positive correlation between CSF and plasma leptin levels (r = 0.81; df = 46; P < 0.0001). This relationship appeared to be linear, and the curve fit was not significantly improved by the use of logarithmic or quadratic curves.
When the ratio of CSF to plasma leptin was plotted against the plasma
leptin concentration, a curvilinear relationship was apparent (Fig. 4A). Thus, low weight anorexic patients had higher
values for the ratio of CSF to plasma leptin concentrations than the
healthy controls (t = 5.43; df = 24;
P < 0.0001; Fig. 4B). The ratio of CSF to plasma
leptin concentration was not significantly different from control
values for anorexic patients studied during the weight restoration and
goal weight phases.
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Given the role of hypothalamic serotonin pathways in postprandial
satiety (24), it was of interest to examine the relationship between
CSF concentrations of leptin and 5-HIAA in the patient and control
groups. Low weight anorexic patients had significantly reduced levels
of 5-HIAA (82 ± 32 ng/mL; n = 10) compared to controls
(106 ± 18 ng/mL; n = 12; t = 2.64; df =
20; P < 0.02). CSF 5-HIAA values for the anorexic
patients increased progressively during the treatment program, as
reflected in measurements during weight gain (85 ± 32 ng/mL) and
at goal weight (100 ± 43 ng/mL). CSF 5-HIAA levels were
significantly correlated with CSF leptin levels for the combined group
of low weight anorexic patients and healthy controls (r = 0.57;
df = 20; P < 0.01; Fig. 5),
although this correlation did not reach significance for controls or
patients taken separately.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have also provided the first information on CSF leptin levels in anorexia nervosa, an idiopathic state of self-induced starvation. Women with anorexia nervosa showed a marked decrease in plasma and CSF leptin concentrations compared to healthy, age-matched female controls, demonstrating that anorexia nervosa does not result from a simple excess of CNS leptin levels, as might occur secondary to enhanced peripheral levels or increased uptake. After weight gain in anorexic patients, leptin levels increased significantly in both plasma and CSF to levels not significantly different from normal. This is the first report of dynamic changes in CSF leptin with changes in nutrition or body weight. These results also substantially extend the findings of two other reports. In one, 10 of 15 patients with anorexia nervosa had plasma leptin levels less than the assay normal range, whereas levels in the remaining 5 were in the normal range (22). In this same report, 5 patients studied longitudinally after weight gain averaging 2.1 kg/m2 had no significant change in plasma leptin levels. The significant increase in leptin levels after weight gain in the current study is likely to reflect the larger weight gain and the larger number of individuals studied. In a second, cross-sectional study (23), serum leptin levels were significantly correlated with body weight and percent body fat in 22 women with anorexia nervosa and were significantly lower than values for healthy female controls.
In the current study, the percent decrease in plasma leptin in low weight anorexics exceeded the percent decrease in their CSF leptin. Thus, the CSF to plasma leptin ratio was markedly elevated in low weight anorexic patients compared to controls. As we were unable to study CSF leptin in similarly low weight individuals with simple starvation, it is unclear whether this effect is a consequence of low body weight associated with malnutrition per se or is a specific feature of anorexic patients. However, a similar increase in the plasma to CSF leptin ratio was observed at low leptin levels in patients without anorexia (20). A significant fraction of leptin in blood is bound to serum proteins (30). Additional studies will be needed to evaluate the relationship between concentrations of free leptin in plasma and CSF in healthy individuals and patients with abnormal regulation of body weight.
It is important to consider the possible relationship between diminished CSF leptin concentrations and the hypothalamic amenorrhea of anorexia nervosa. Leptin has been linked to control of reproduction in three ways. First, female ob/ob mice with leptin deficiency have hypothalamic amenorrhea and infertility, and chronic treatment with recombinant leptin can restore fertility (31). Second, the reduction in leptin levels during starvation of normal mice contributes to abnormalities in the hypothalamic-pituitary-adrenal and gonadal axes, as leptin administration prevented the delay in reproductive cycling in this model (32). Third, administration of leptin can accelerate the onset of puberty in normal mice (33, 34). If the physiology of leptin is similar in humans, treatment with leptin might restore fertility in low weight women with anorexia nervosa. Even if amenorrhea in low weight patients could be treated in this manner, however, the possibility of other adverse consequences of leptin administration (e.g. delayed weight gain) would need to be carefully evaluated.
An important observation in the current study was that as the anorexic patients gained weight, CSF and plasma leptin concentrations reached levels equivalent to normal values, whereas the patients were still at a significantly lower weight than the controls. This result can be understood in terms of our previous observation that anorexic patients participating in a behaviorally oriented weight restoration program with progressive augmentation of caloric intake experience a relatively rapid increase in percent body fat (27). Taken together, these findings suggest that rapid normalization of leptin levels during weight restoration is probably due to disproportionate accumulation of fat during the refeeding period and may contribute to the difficulty anorexic patients experience in achieving and maintaining a normal weight.
The finding of decreased CSF levels of the serotonin metabolite 5-HIAA in the low weight anorexia nervosa patient group is consistent with previously reported findings (35, 36). It is of interest that the present results demonstrated a significant positive correlation between indexes of two neurochemical systems thought to limit food intake. Additional investigations are needed to study the possible interactions between leptin and serotonin, neuropeptide Y, galanin, and other neurochemicals involved in the regulation of eating behavior.
In summary, this study has provided several new insights into the regulation of CSF leptin. First we have shown that in normal subjects, CSF leptin correlates better with BMI than does plasma leptin, consistent with the ability of leptin in CSF to integrate plasma levels that may be subject to short term fluctuations. Second, we confirm a prior report that the ratio of CSF/plasma leptin is markedly increased at low plasma leptin levels, consistent with increased efficiency of CSF uptake under these conditions. We also provide the first demonstration that this increased ratio decreases during weight gain. Finally, we demonstrate that patients with anorexia at low weight have reduced CSF leptin compared to controls and that they normalize their CSF (and plasma) leptin levels during weight gain at a point before achieving normal body weight, as assessed by BMI. This could result from the tendency of these patients to regain weight disproportionately as fat and could contribute to their resistance to regaining normal body weight and composition.
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Acknowledgments |
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Footnotes |
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2 Member of the Clinical Investigators Training Program, Beth Israel
Hospital-Harvard-Massachusetts Institute of Technology, Department of
Health Science and Technology, in collaboration with Pfizer.
Received December 10, 1996.
Revised February 20, 1997.
Accepted March 5, 1997.
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) to the weight gain phase (
) and goal weight
phase (•). Patients reached an average leptin level similar to that
in 15 controls (
), even though their body weight (BMI) remained
significantly lower than that in the controls. B, For 7 anorexic
patients (compared to 6 controls) for whom anthropometries were
available, CSF leptin values increased proportionately to the increase
in percent body fat. Values are the mean ± SE.
