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Original Studies |
Department of Psychiatry, University of Minnesota (E.D.E., N.R., P.T.), Minneapolis, Minnesota 55455; the Department of Internal Medicine, University of Kentucky (C.P.), Lexington, Kentucky 40536; and the Department of Medicine and General Clinical Research Center, Tulane University (P.F.K., C.Y.B.), New Orleans, Louisiana 70112
Address all correspondence and requests for reprints to: Elke D. Eckert, M.D., Department of Psychiatry, University of Minnesota Hospital, Box 393, Mayo Building, Minneapolis, Minnesota 55455.
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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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Anorexia nervosa is a serious eating disorder characterized by decreased caloric intake, increased physical activity, chronically low weight, and resistance to efforts to increase body weight. The pathogenesis of this potentially fatal illness remains poorly understood. Multiple abnormalities of the neuroendocrine system, in large part thought to reflect starvation-induced changes, include activation of the hypothalamic-pituitary-adrenal axis and suppression of the thyroid and gonadal axes (11). In addition, there is an alteration of the GH-insulin-like growth factor (GH-IGF) axis, with down-regulation of the GH receptor or its postreceptor mechanisms leading to increased pituitary GH secretion and suppressed IGF-I (12, 13).
Reports of studies of leptin in patients with anorexia nervosa are limited. Two published studies demonstrate significantly reduced serum leptin levels in anorectics at low body weights before refeeding, but the exact relationship of leptin to body weight in anorexia nervosa remains unclear (14, 15). In the first study, no clear relation was evident between leptin and body mass index (BMI) (14). In the second study, there was a linear correlation of leptin levels with BMI, percent body fat, and IGF-I with progressively lower leptin levels as BMI diminished (15). The authors of the second study concluded that the normal physiological regulation of leptin is maintained in malnourished anorectics. It is not known whether leptin regulation differs in starvation (anorectics before refeeding) compared to normal nutritional states (anorectics after weight gain and/or normal weight controls). The anorectics in the second study were not studied after nutritional rehabilitation. Our study was designed to clarify the exact relationship between leptin and body weight in anorexia nervosa before and after treatment and weight gain.
We hypothesized that in anorexia nervosa, leptin may be dysregulated in response to starvation, perhaps related to changes in as yet unidentified hormones, and this may contribute to the pathogenesis of anorexia nervosa. To further clarify the regulation and physiological role of leptin in anorexia nervosa, we studied serum leptin and its relationship to BMI, IGF-I, GH, and other relevant hormones in female anorectics at low weights when they were admitted to a hospital or partial hospital treatment program and again after weight gain in these intensive treatment programs. We compared the results to those in healthy, normal weight control females.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects with anorexia nervosa were recruited from the in-hospital and partial hospital program of the University of Minnesota Eating Disorders Program. Female patients at least 16 yr of age who were less than 80% of ideal body weight, met Diagnostic and Statistical Manual of Mental Disorders IV criteria for anorexia nervosa (16), and provided informed consent (including parental consent for minors) were eligible for the study. Control subjects were healthy women recruited from the general population by newspaper advertisement. Control subjects had to be between 90–125% of ideal body weight and could not have had an eating disorder or other major psychiatric illness. Neither controls nor anorectic subjects had thyroid disease or diabetes mellitus, nor were they taking any medications known to affect fat metabolism or the nutritional state.
Twenty-nine female anorectic subjects and 15 normal weight, healthy
control female subjects were enrolled and studied (Table 1
). The mean age of the anorectics was
25.8 ± 8.1 yr (range, 16–43) and was not significantly different
from the mean age of 30.1 ± 6.8 yr (range, 19–41) of the healthy
female controls. Ideal body weights were determined by the 1959
Metropolitan Life Insurance Co. tables (17).
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Anorectic subjects were treated with the regular in-hospital and/or partial hospital eating disorder programs that addressed nutritional rehabilitation and normalization of eating behaviors according to a systematized approach, which included an expectation of a 0.5 lb/day increase in the hospital and 2 pounds/week in the partial hospital program. Subjects almost always complied with the expectation to complete dietitian-approved meals or their equivalent in a liquid nutrient, as behavioral consequences, such as being tube fed, for noncompliance were used. No hyperalimentation was used.
Venipuncture was performed once for control subjects and twice for anorectics: during the first 2 days after hospital admission (baseline untreated; n = 29) and again after a period of nutritional rehabilitation just before discharge (after body weight gain; n = 21). Venipuncture was performed from 1–3 h after a 300- to 500-Cal meal was completed; generally between 0900–1100 h. Serum samples were stored at -70 C.
Serum leptin levels were assessed by RIA (Linco Research, St. Charles, MO), with an intraassay coefficient of variation of 3.4–8.3% and a sensitivity of 0.5 ng/mL. Serum IGF-I was assessed after acid-alcohol extraction by RIA (Nichols Institute Diagnostics, San Juan, CA). The intra- and interassay variations were 4.8% and 10.1%, respectively. Serum GH levels were measured by the immunoradiometric assay of Nichols Institute Diagnostics. The sensitivity of the assay was 0.2 µg/L; intra- and interassay coefficients of variation were 4.22% and 7.2%, respectively. Samples were assayed in duplicate. Cortisone, LH, FSH, transferrin, insulin, and total estrogen were assessed by standard laboratory methods.
Body weights and nutritional status of subjects (Table 1
)
The BMI of the untreated anorectics at admission (15.3 ± 2.0; range, 10.7–17.8) was significantly lower (P < 0.001) than the BMI of the controls (22.3 ± 1.8; range, 19.7–25.2). Twenty-one of the 29 anorectics were restudied after treatment and body weight gain in the hospital and/or partial hospital program when they had increased their body weight by 5.9 ± 4.3 kg (range, 1.8–18.0 kg). These 21 anorectics had significantly increased their BMIs (P < 0.001), although they were still significantly lower than the control values (P < 0.001).
The anorectics at hospital admission had evidence of nutritional impairment, with serum transferrin of 271.3 ± 76.4 mg/dL (n = 24) compared to 313.7 ± 50.2 mg/dL (n = 13) in the controls (P = 0.09). An increase in transferrin paralleled an increase in body weight gain, so that after treatment, the transferrin level was 288.2 ± 46.5. This was not significantly different from the control value, but was significantly increased from baseline (P < 0.05).
Data analysis
Data are expressed as the mean ± SD. Independent Student’s t tests were used to compare age, subgroups of anorectics, BMI, leptin, IGF-I, GH, and other parameters between anorectics and controls. Comparisons between anorectics at the two time points were performed using matched pair t tests. Using linear models, serum leptin was regressed on BMI separately for controls, for starving anorectics at baseline, and for anorectics after weight gain. Serum leptin was regressed on IGF-I, controlling for BMI.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). After body weight gain,
leptin levels in anorectics had significantly increased
(P < 0.01) by 2.3 ± 3.3 ng/mL (range, 0.9–12.8
ng/mL), but leptin levels were still significantly below those of the
normal body weight controls (5.6 ± 3.8 vs. 12.0
± 6.9 ng/mL; P < 0.05).
The relationship of leptin to BMI is shown in two separate comparisons
(Fig. 1, A and B). Figure 1A shows the
relationship of leptin to BMI in the starved anorectics at baseline
compared with that in the normal weight controls. Controls showed a
very strong linear correlation (r = 0.76; P <
0.001). In contrast, no significant linear correlation was found in the
anorectics at baseline (r = 0.18). The data suggest that at very
low BMIs, there is a threshold beneath which leptin cannot decrease and
hence appears to uncouple from BMI in a nonlinear relationship. This
threshold effect appears to occur at a BMI between 14–17. Figure 1B
shows that after weight gain, anorectics displayed a strong linear
correlation between leptin and BMI (r = 0.69; P <
0.001), similar to that in the controls. However, it is noteworthy that
in weight-recovering treated anorectics with BMIs above about 17, the
leptin to BMI ratio was higher than that in controls at similar
BMIs.
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Untreated anorectics at hospital admission had significantly lower (P < 0.001) serum IGF-I levels (186.6 ± 69.7 µg/L) compared to controls (333.33 ± 84.4 µg/L), again reflecting the poor nutritional state of the anorectics before treatment. As anorectics gained body weight, their IGF-I levels increased progressively and significantly (P < 0.001) toward normal. After body weight gain, IGF-I levels in the anorectics were no longer significantly lower than those in the controls. IGF-I was correlated with BMI in the anorectics before treatment (r = 0.47; P < 0.01), but this correlation diminished and failed to reach statistical significance when analyzed after body weight gain. IGF-I was not significantly correlated with BMI in the controls.
Serum leptin levels showed a substantial linear correlation with IGF-I in the anorectics at baseline (r = 0.63; P < 0.001) even after controlling for BMI (r = 0.63; P < 0.001) in a regression analysis. After the anorectics gained body weight, the correlation of leptin with IGF-I approached significance (r = 0.4; P < 0.09), but was not significant after controlling for BMI. Among the normal body weight controls, leptin did not correlate significantly with IGF-I.
The mean GH levels were higher in the untreated compared with the treated anorectics and compared with the control values. However, there was much variability in GH levels, and the differences were not statistically significant. Mean FSH, total estrogens, and LH levels were low, as expected in the starved anorectics, but only LH was significantly lower compared with that in controls (P < 0.05). Serum cortisol was nonsignificantly elevated in starved anorectics compared with controls, but significantly decreased with body weight gain (P < 0.01). Serum leptin did not correlate significantly with total estrogens, LH, FSH, GH, or cortisol in the anorectics before treatment.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, there is a lack of significant correlation of leptin with BMI when anorectics were at extremely low BMIs during starvation. This agrees with the report of 14 female anorectics by Hebebrand et al. (14), but contradicts the results of the study by Grinspoon et al., which found a significant linear correlation of leptin with BMI (15). This discrepancy could be accounted for by the fact that our subjects had lower BMIs than those reported by Grinspoon et al. In the Grinspoon et al. study, there were no subjects with a BMI below 13, whereas our study included five subjects with BMIs below 13 who still had substantial leptin levels (average, 3.02 ng/mL). We conclude that the most likely explanation for the lack of significant correlation in our study is that there is a threshold beyond which leptin cannot decrease physiologically. However, it remains possible that other factors explain this uncoupling or apparent leveling off of leptin with extremely low BMIs.
Our data show that after nutritional rehabilitation and body weight gain there is a significant increase in leptin toward that in normal controls, as would be expected physiologically. However, anorectics are still below normal controls in body weight and serum leptin. The similarity of the positive correlation of leptin with body weight in our weight-recovering anorectics and our normal body weight controls is further supportive evidence that there is a normal physiological response of leptin to weight gain in anorexia nervosa.
Our findings raise the possibility that leptin levels were actually higher than predicted, i.e. dysregulated, in the malnourished subjects and in the weight-recovering subjects. The results indicate that recovering anorectics tended to have higher leptin levels than controls of comparable body weights. It is not known whether leptin levels are higher than predicted in normal subjects with involuntary starvation or extremely low BMIs. A relative increase in serum leptin in the anorectics could mean that factors other than body weight or percent body fat have an independent effect on the physiological regulation of leptin secretion during starvation. Previous studies have shown that insulin (18, 19), proinflammatory cytokines (20, 21), and possibly corticosteroids (22) and GH (22, 23) stimulate the release of leptin and appear to have a role in regulating serum leptin, independently of changes in body fat. Ahima et al. recently proposed that during starvation, regulation of the neuroendocrine system could be the main physiological role of leptin (24). Although our data did not show a relationship of cortisol and GH to leptin, in previous studies of untreated anorectics, proinflammatory cytokines (25), cortisol (11), and GH (11) have been shown to be elevated.
In our untreated female anorectics, as previously reported by Grinspoon et al. (15), leptin was highly correlated with IGF-I, even after controlling for BMI. In our study, this was no longer true, as the body weight of the anorectics increased toward normal, and it was not true in normal body weight control females. The linkage of leptin to the growth factor IGF-I during starvation supports the previous observations that insulin and possibly GH and corticosteroids have an independent association with the physiological regulation of leptin during starvation (18, 19, 22, 23).
A major limitation of this study is the lack of data on percent body fat. The lack of correlation of leptin with BMI in untreated anorectics in our study, especially those at very low BMIs, does not rule out a correlation of leptin with percent body fat at low BMIs and hence a maintenance of the normal physiological regulation of leptin in starvation. Nevertheless, an uncoupling is certainly possible and is consistent with a recent study showing that during a long term hypocaloric diet, leptin uncouples from changes in body fat mass (26).
The data from this study suggest that in starved female anorectics at very low body weights, serum leptin levels are reduced significantly, but appear to dysregulate or uncouple from body weight in a nonlinear relationship. This probably represents a threshold effect. Leptin increases with weight gain, suggesting a normal physiological response of leptin to weight gain in anorectics. However, leptin levels tended to be higher in weight-recovering anorectics than in controls of comparable body weight. This raises the possibility that leptin levels, although in the normal range, may be pathologically elevated. Such a pathological elevation or dysregulation could be related to the neuroendrocrine abnormalities seen in starvation and possibly to the difficulties with weight restoration and maintenance in severe anorexia nervosa.
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Acknowledgments |
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Footnotes |
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Received August 18, 1997.
Revised November 11, 1997.
Accepted December 3, 1997.
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References |
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