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Reduction of Plasma Leptin Levels and Loss of Its Circadian Rhythmicity in Hypocretin (Orexin)-Deficient Narcoleptic Humans

Departments of General Internal Medicine, Neurology (S.O., G.J.L.), and Endocrinology (F.R.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: S. W. Kok, M.D., Leiden University Medical Center, Department of General Internal Medicine (C1-R38), P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: s.w.kok{at}lumc.nl

Abstract

Recent observations have implicated hypocretin deficiency in the pathogenesis of narcolepsy. Hypocretin neurotransmission also affects energy balance, and narcoleptic patients tend to become obese. Because hypocretins appear to have important neuroendocrine effects, we hypothesized that the neuroendocrine systems that regulate energy balance might be distinctly set in narcolepsy. As leptin is a pivotal part of these systems, we explored the 24-h plasma leptin (20-min sampling interval) concentration profile in six narcoleptic males and six normal controls, matched for age, sex, body mass index, waist/hip ratio, and fat mass. We thus demonstrated a reduction of the mean 24-h leptin concentration in narcoleptics to 52% of that in controls (5.9 µg/liter in narcolepsy vs. 11.4 µg/liter in controls; P < 0.05). Further, a nocturnal acrophase (clock time of the highest concentration), which is typical of normal leptin secretion, was observed in controls (mean, 2335 h; 95% confidence interval, 2105–0205 h), but not in narcoleptic patients. The mechanisms that potentially disturb the circadian rhythm of leptin levels in hypocretin-deficient narcoleptic humans include anomalies of the sleep-wake cycle and/or disruption of the circadian distribution of autonomic activity. As leptin deficiency clearly leads to morbid obesity in experimental animals and humans, we infer that the observed reduction of plasma leptin levels may predispose narcoleptic humans to weight gain.

NARCOLEPSY IS a debilitating neurological disease, characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis (1). Its prevalence amounts to 0.05% in the U.S. and Europe (2). Recent studies have established deficiencies in hypocretin (orexin) neurotransmission to be the cause of narcolepsy. Mutations in hypocretin receptor 2 evoke narcoleptic symptoms in a canine model, and mice with a targeted deletion of the prepro-hypocretin gene display a phenotype strikingly similar to that of human narcolepsy (3, 4). Recently, genetic ablation of hypocretin neurons was shown to result in narcolepsy in mice (5). Moreover, hypocretin-1 is undetectable in the cerebrospinal fluid (CSF) of the majority of narcoleptic humans, whereas hypocretin peptides are absent, and the number of hypocretin neurons is considerably reduced in narcoleptic human brains (6, 7). Based on the tight association of human narcolepsy and the human leukocyte antigen subtype DQB1*0602, a highly selective autoimmune-mediated destruction of hypocretin neurons is thought to underlie the disease (2, 7).

The hypocretins (1 and 2), also called orexin A and B, are two neuropeptides encoded by the prepro-hypocretin gene (8, 9). Hypocretin-1 is a 33-amino acid 3562-Da peptide with two intrachain disulfide bonds, and human hypocretin-2 is a 28-amino acid peptide with a molecular mass of 2937 Da (1, 10). Hypocretins are produced by a small group of neuronal cell bodies located in the lateral and posterior hypothalamus and parafornical nucleus, a region of the brain that is involved in the regulation of energy metabolism (7, 11). These neurons have extensive projections throughout the entire nervous system and have been implicated as important regulators of wakefulness, autonomic nervous system tone, and neuroendocrine secretion, as well as feeding behavior and energy expenditure (11).

Therefore, it is no surprise that hypocretin peptides were initially identified as stimulants of feeding behavior (8). Subsequently, it was reported that hypocretins promote sympathetic outflow and basal metabolic rate (12, 13). Thus it is conceivable that, aside from its influence on feeding, hypocretin deficiency disrupts energy balance (13, 14). Indeed, narcolepsy induced by ablation of hypocretin neurons in orx-ataxin 3 transgenic mice, a model which closely resembles the putative pathogenesis in humans, is marked by late-onset obesity despite a reduction in food intake (5). Several reports indicate an increased prevalence of obesity and obesity-related disorders in narcoleptic patients (15, 16, 17). Thus, hypocretin deficiency appears to be associated with changes in energy balance in experimental animals as well as in humans.

In view of hypocretins’ ability to modulate neurohormone secretion, we hypothesized that the neuroendocrine systems regulating energy balance might be distinctly set in hypocretin-deficient narcoleptic humans. Leptin is a major component of these systems, and a recent study reported diminution of the plasma leptin concentration in a single fasting blood sample in narcoleptic humans (18). The plasma leptin concentration displays circadian rhythmicity (19, 20), and the (circadian) variation of the plasma concentration of hormones, in addition to their average level, has been demonstrated to be important for their biological action (21). Thus, it is conceivable that hypocretin deficiency affects energy balance through modulation of the circadian rhythmicity of the plasma leptin concentration. We therefore measured 24-h plasma leptin levels and factors regulating leptin secretion in hypocretin-deficient narcoleptic humans and in healthy controls who were individually matched for age, gender, body mass index (BMI), and fat mass.

Subjects and Methods

Subjects

Six male patients from the out-patient clinic of the Department of Neurology were enrolled in the study. The diagnosis of narcolepsy with cataplexy was made on clinical grounds by a physician experienced with narcolepsy (G.J.L.). Multiple sleep latency testing showed results typical for narcolepsy (1). All patients were human leukocyte antigen DR2/DQB1*0602 positive and lacked hypocretin-1 in their CSF [measurements as previously described (6)]. Sleep registration during the study, using a portable electroencephalogram system (Porti, Twente Medical Systems, Enschede, NL), confirmed abnormally distributed 24-h total sleep as well as rapid eye movement (REM) sleep in narcoleptic subjects, whereas the various sleep stages were normally distributed in control subjects, none of whom showed daytime sleep. All subjects were free of medication or (in three patients) discontinued medication for at least 2 wk before study. Of these, three narcoleptic subjects two used psychostimulants (methylfenidate and modafinil), and one used a tricyclic antidepressant (clomipramine). Control subjects were recruited by advertisements in local newspapers. The weight and height of each subject were measured. Waist was measured in centimeters halfway between the lowest rib and the crista iliaca, and hip was measured as the maximum circumference of the hips in the standing position in centimeters. The waist to hip ratio was used as a relative measure of abdominal fat mass. Total body fat mass was determined by dual energy x-ray absorptiometry (QDR 4500, Hologic, Inc., Waltham, MA) (22). Subjects were matched for sex, age, BMI, total fat mass, and waist/hip ratio. Subjects were eligible for the study after exclusion of hypertension (defined as a repeated blood pressure measurement of systolic >140 mm Hg and diastolic >90 mm Hg), any known (history of) pituitary disease, recent weight change (>3 kg weight gain or loss within the last 3 months), and fasting blood glucose greater than 7.0 mmol/liter. Written informed consent was obtained from all subjects. The study was approved by the ethics committee of the Leiden University Medical Center.

Clinical protocol

On the morning of the 24-h study, subjects were admitted to the Clinical Research Center. During this occasion three standardized meals were served at 0900, 1300, and 1800 h (Nutridrink, 1.5 kcal/ml, 1500–1800 kcal/d; macronutrient composition per 100 ml: 5 g protein, 6.5 g fat, and 17.9 g carbohydrate; Nutricia, Zoetermeer, NL). Subjects remained sedentary except for bathroom visits; at 2300 h lights were switched off. Blood was collected at 20-min intervals for determination of the serum leptin concentration. Blood samples were taken from an antecubital vein with S-monovetten (Sarstedt, Etten-Leur, NL) as follows. An iv cannula was attached to a three-way stopcock that was attached to a continuous saline infusion to keep the cannula clot-free. Sampling was performed from the three-way stopcock by a distant tubing at the subject’s bedside to prevent sleep disturbance by investigative manipulations. All urine produced during the 24-h study was collected for determination of catecholamine concentrations. Fasting plasma concentrations of cortisol, insulin, and glucose were determined on a separate occasion within 3 wk of the 24-h sampling experiment.

Assays

Plasma human leptin concentrations were determined with a standardized RIA (Linco Research, Inc., St. Charles, MO); the limit of detection was 0.5 µg/liter. The intraassay coefficients of variation ranged from 6–7% over the leptin concentration range of 3–80 µg/liter, and the interassay coefficients of variation were 10.2%, 5.3%, and 7.2% for concentrations of 3.9, 11.3, and 63.8 µg/liter. All samples of one 24-h profile were processed in the same assay procedure.

Plasma cortisol and insulin were measured by RIA (Medgenix, Fleurus, Belgium). Serum glucose and urinary creatinine were measured using a fully automated Hitachi 747 system (Hialeah, FL). Urinary catecholamines were measured by HPLC with electron capture detection.

Calculations and statistics

Cosinor analysis. Nyctohemeral secretion of leptin was analyzed using cosinor analysis, an algorithm that fits to the sum of a cosine wave and a straight line using repeated nonlinear regression analysis (23). This analysis defines an acrophase, which is the clock time during 24 h at which the concentration of the investigated hormone is maximal; a mesor, which is the average value about which the diurnal rhythm oscillates; and an amplitude, which is half the absolute difference between the nadir and the peak value of the 24-h concentration series.

Statistical analysis. Results are expressed as the mean ± SEM unless stated otherwise. A paired, two-tailed t test was used to compare groups. One-way ANOVA to compare more than two groups was used to analyze the differences in nocturnal increase in leptin concentration between groups. Differences were considered significant at P < 0.05. Statistical analysis was performed using SPSS for Windows (release 9.0, SPSS, Inc., Chicago, IL).

Results

The characteristics of the participants are given in Table 1. Controls were closely matched to narcoleptic patients with regard to age, BMI, and waist circumference. Individual total body fat percentages of all participants ranged from 12.9–30.4%. The percent body fat was slightly, but not significantly (P = 0.07; mean difference, -2.6%), lower in narcoleptic subjects. A linear regression analysis did not reveal a statistical association between the size of the difference in body fat percentage and the difference in mean leptin concentration in narcoleptic vs. healthy control subjects (P = 0.77). The mean BMI of the subjects was in the overweight range (mean BMI, 28.3 kg/m²; overweight range, 25–30 kg/m²), as expected in narcoleptic patients.

View larger version (42K): [in this window] [in a new window]   Figure 1. Circadian rhythm of the mean 24-h leptin concentration in narcoleptics (triangles) and controls (circles). Data are the mean ± SE. Leptin concentrations in narcoleptic patients remain lower during the 24 h, and no noctural rise is observed. The mean leptin concentration in control subjects during the daytime, defined as the period from 0700–1900 h, is 11.0 µg/liter and rises to a mean of 12.0 µg/liter at night, defined as the period from 1900–0700 h, an increase of 9.8%. In the narcoleptic patients the leptin concentration has a mean daytime value of 6.4 µg/liter and a nighttime value of 5.7 µg/liter, a decrease of 7.8% (P = 0.036, comparing increase at night in controls vs. narcoleptic subjects).

The present study documents profound changes in leptin plasma concentrations and circadian rhythmicity in hypocretin-deficient narcoleptic humans. The 24-h leptin concentration profile in narcoleptic patients is characterized by decreased mean plasma leptin concentrations. Furthermore, the normal circadian rhythm of plasma leptin levels, typically marked by a nocturnal acrophase, is absent in narcolepsy. These findings suggest that hypocretin deficiency affects neuroendocrine systems that set the height of the leptin concentration and its circadian rhythmicity. As leptin deficiency clearly leads to morbid obesity in experimental animals and humans, we infer that the observed anomalies may predispose narcoleptic humans to weight gain (24, 25).

The reduction of the mean 24-h leptin concentration in narcoleptic patients (52% of that in healthy controls) corroborates the results of a previous study, which demonstrated that the plasma leptin concentration in a single fasting blood sample is lower in narcoleptic humans than in controls (18). The mechanism underlying hypoleptinemia in narcolepsy remains to be established. Fat mass is a major determinant of plasma leptin concentrations. The mean total body fat percentage was slightly lower in our narcoleptic patients (2.6% of total body weight) compared with that in the controls. Although this difference is small and not statistically significant, it probably impacts circulating leptin levels in narcoleptics to some extent. However, it is not likely to be a major factor explaining the reduction of leptin levels in narcolepsy for at least two reasons. First, the difference is very small compared with the difference in the average leptin concentration (50%). Secondly, linear regression analysis did not reveal an association between the difference in body fat percentage and the difference in circulating leptin levels in both groups; leptin levels are also lower in narcoleptic subjects with higher fat percentages than their matched controls. Superimposed on the regulation by fat mass, leptin production and secretion by adipocytes are governed by various metabolic and neurohormonal factors. In particular, short-term regulatory influence has been attributed to nutritional status, cortisol, and sympathetic tone (26, 27, 28). However, none of these neurohormonal modulators of leptin production differed significantly between the groups, although it is important to emphasize that the number of subjects we studied is probably too small to allow definite conclusions with respect to these variables. Thus, our data do not provide a satisfactory explanation for the reduction of the mean 24-h leptin concentration that we observed in narcolepsy.

The loss of circadian rhythmicity, a second characteristic of the 24-h plasma leptin profile in hypocretin deficiency demonstrated in our study, may relate to the disruption of the diurnal patterns of sympathetic tone that has been observed in narcoleptic humans (29). A recent study in rats has demonstrated that the diurnal rhythm of plasma leptin concentration is generated by the suprachiasmatic nucleus (SCN), which is the location of the biological clock in mammals (including humans) (30). It was proposed that the effects of the SCN on leptin secretion were mediated by the autonomic nervous system (30). As the SCN projects to hypocretin neurons (31), and hypocretins clearly activate the sympathetic nervous system, it is tempting to speculate that hypocretin neurons mediate part of the influence of the SCN on the circadian distribution of autonomic activity (14). If true, hypocretin deficiency would be predicted to disrupt the SCN-mediated circadian rhythm of autonomic function, which may impact leptin rhythmicity.

Alternatively, the narcoleptic pattern of sleep-wakefulness may disrupt the normal sleep-mediated nocturnal reduction in sympathetic tone and thereby blunt the nocturnal rise of leptin levels (29). Sympathetic nerve activity normally decreases during the first hours of sleep in non-REM sleep stage IV, which agrees with the timing of the nocturnal leptin peak (32). Narcoleptic patients display a disruption of the circadian distribution of distinct sleep stages and fragmentation of sleep (33), which may compromise the circadian rhythmicity of sympathetic tone and thereby affect the circadian rhythm of leptin. Indeed, the diurnal rhythm of plasma leptin appears to be sensitive to the phase-shifting of sleep (34), and sleep deprivation is associated with a considerable reduction of the plasma leptin concentration in healthy adults (35).

Regardless of the mechanism, reduced circulating leptin levels and disrupted circadian rhythmicity in narcoleptics may contribute to their tendency to grow obese. Leptin modulates energy balance through numerous neuroendocrine pathways that are coordinated in hypothalamic nuclei (36). The absence of functional leptin strongly stimulates food intake and reduces energy expenditure in both experimental animals and man (37, 38). Leptin-deficient mammals are therefore (morbidly) obese. It is conceivable that a relative reduction of circulating leptin levels exerts similar (but less extreme) effects. In apparent contrast with this idea is our earlier observation of reduced food intake in narcoleptic humans, which was corroborated by a recent study in hypocretin neuron-ablated mice, which are obese despite being hypophagic (5, 39). However, as hypocretins appear to be part of the complex neural networks that convey the leptin signal to the brain (14, 40), it is tempting to speculate that the absence of bioactive hypocretin somehow counterbalances the potential effect of hypoleptinemia on food intake, whereas the effect of hypoleptinemia on energy expenditure remains unabated. Recent data demonstrate a reduced basal metabolic rate in hypocretin knockout mice (41). The circulating leptin level in these animals is unknown.

As far as we are aware, the present data are the first to document diminution of plasma leptin levels with an abrogated circadian rhythm as a feature of a human disease that is marked by obesity (apart from the few humans that have leptin gene defects). If it is found that hypoleptinemia indeed plays a role in the development of obesity in narcoleptic patients, the present findings may have much broader implications for the pathogenesis of human obesity. Although fat mass is the main determinant of the plasma leptin concentration, the plasma leptin level per kg fat tends to vary greatly among (obese) humans (42). Reduced leptin expression and/or secretion by adipocytes, induced by distinct settings of regulatory systems, may then be involved in the tendency of some patients to become obese.

In conclusion, the present study suggests that the neuroendocrine systems that set the height of the leptin concentration and its circadian rhythmicity are altered in hypocretin-deficient narcoleptic humans. The influence of disrupted circadian distribution of REM/non-REM sleep and/or disrupted signaling of the SCN on sympathetic tone may be involved in the disturbance of the leptin circadian rhythm in narcoleptic patients. The changes may be involved in the pathogenesis of obesity that often accompanies narcolepsy.

Acknowledgments

We gratefully acknowledge the efforts of the following persons in the completion of this study: S. Nishino, M.D. (University School of Medicine, Stanford, CA), for the measurements of CSF hypocretin-1 concentrations; A. Vein, M.D. (Leiden University Medical Center), for performing the sleep registrations; and E. J. M. Ladan-Eygenraam for the technical support.

Footnotes

Abbreviations: BMI, Body mass index; CSF, cerebrospinal fluid; REM, rapid eye movement; SCN, suprachiasmatic nucleus.

Received July 30, 2001.

Accepted October 31, 2001.

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