leptin and Narcolepsy

Narcolepsy, a sleep disorder characterized by loss of hypocretin neurons, has been associated with metabolic disturbances. Although the metabolic alterations in narcolepsy patients are widely investigated in the literature, the results are controversial. We performed a systematic search of literature to identify metabolic profiling studies in narcolepsy patients. A total of 48 studies were included in the meta-analysis. Narcolepsy patients exhibited higher prevalence of obesity (log OR = 0.93 [0.73-1.13], P < 0.001), diabetes mellitus (log OR = 0.64 [0.34, 0.94], P < 0.001), hypertension (log OR = 0.33 [0.11, 0.55], P < 0.001), and dyslipidemia (log OR = 1.19 [0.60, 1.77], P < 0.001) compared with non-narcoleptic controls. Narcolepsy was associated with higher BMI (SMD = 0.50 [0.32-0.68], P < 0.001), waist circumference (MD = 8.61 [2.03-15.19], P = 0.01), and plasma insulin (SMD = 0.61 [0.14-1.09], P = 0.01). Levels of fasting blood glucose (SMD = -0.25 [-0.61,0.10], P = 0.15), BMR-RMR (SMD = -0.17 [-0.52-0.18], P = 0.34), systolic blood pressure (SMD = 0.29 [-0.39-0.97], P = 0.40), diastolic blood pressure (SMD = 0.39 [-0.62, 1.40], P = 0.45), CSF melanin-concentrating hormone (MD = 5.56 [-30.79-41.91], P = 0.76), serum growth hormone (SMD = 7.84 [-7.90-23.57], P = 0.33), as well as plasma and CSF leptin (SMD = 0.10 [-1.32-1.51], P = 0.89 and MD = 0.01 [-0.02-0.04], P = 0.56, respectively) did not significantly differ between narcolepsy patients and controls. These findings necessitate early screening of metabolic alterations and cardiovascular risk factors in narcolepsy patients to reduce the morbidity and mortality rates.

Topics: Humans; Leptin; Metabolome; Narcolepsy; Obesity; Orexins; Sleep Wake Disorders

Narcolepsy is a disabling disease with a prevalence of 0.05%. It is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnogogic hallucinations, automatic behavior, and disrupted nocturnal sleep. The presentation can be very variable, making diagnosis difficult. Loss of hypocretin containing neurons in the lateral hypothalamus has been noted in autopsy studies, and the cerebrospinal fluid level of hypocretin is reduced in patients with narcolepsy with cataplexy. New treatment options are available for the many symptoms of this disease. Early recognition and treatment can greatly improve the quality of life of patients with narcolepsy. A detail review of the epidemiology, pathophysiology, and management of narcolepsy in children is presented.

Topics: Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Child; Dextroamphetamine; Ghrelin; Hallucinations; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Methylphenidate; Modafinil; Narcolepsy; Neuropeptides; Orexins; Polysomnography; Randomized Controlled Trials as Topic; Sleep, REM; Sodium Oxybate

Hypocretin (orexin) peptides are involved in the regulation of energy balance and pituitary hormone release. Narcolepsy is a sleep disorder characterized by disruption of hypocretin neurotransmission. Pituitary LH secretion is diminished in hypocretin-deficient animal models, and intracerebroventricular administration of hypocretin-1 activates the hypothalamo-pituitary-gonadal axis in rats. We evaluated whether hypocretin deficiency affects gonadotropin release in humans. To this end, we deconvolved 24-h serum concentrations of LH and FSH in seven hypocretin-deficient narcoleptic males (N) and seven controls (C) matched for age, body mass index, and sex. Basal plasma concentrations of testosterone, estradiol, and sex hormone-binding globulin were similar in both groups. Mean 24-h LH concentration was significantly lower in narcolepsy patients [3.0 +/- 0.4 (N) vs. 4.2 +/- 0.3 (C) U/l, P = 0.01], which was primarily due to a reduction of pulsatile LH secretion [23.5 +/- 1.6 (N) vs. 34.3 +/- 4.9 (C) U.l(-1).24 h(-1), P = 0.02]. The orderliness of LH and FSH secretion, quantitated by the approximate entropy statistic, was greater in patients than in controls. In contrast, all other features of FSH release were similar in narcoleptic and control groups. Also, LH and FSH secretions in response to intravenous administration of 100 microg of GnRH were similar in patients and controls. These data indicate that endogenous hypocretins are involved in the regulation of the hypothalamo-pituitary-gonadal axis activity in humans. In particular, reduced LH release in the face of normal pituitary responsivity to GnRH stimulation in narcoleptic men suggests that hypocretins promote endogenous GnRH secretion.

Topics: Adult; Carrier Proteins; Entropy; Fluorescent Antibody Technique; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Luteinizing Hormone; Male; Middle Aged; Narcolepsy; Neuropeptides; Orexins; Radioimmunoassay; Testosterone

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Body Mass Index; Carrier Proteins; Energy Metabolism; Female; HLA-DQ Antigens; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Narcolepsy; Neuropeptides; Orexins

Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones.. Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night).. At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones.. The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion.

Topics: Adjuvants, Anesthesia; Adult; Body Composition; Body Mass Index; Ghrelin; Humans; Leptin; Male; Narcolepsy; Obesity; Sodium Oxybate

The possible relationship between cerebrospinal fluid (CSF) hypocretin and leptin levels, overweight, and association to risk factors for diabetes 2 in narcolepsy with cataplexy were compared to patients with idiopathic hypersomnia and controls.. 26 patients with narcolepsy, cataplexy, and hypocretin deficiency; 23 patients with narcolepsy, cataplexy, and normal hypocretin values; 11 patients with idiopathic hypersomnia; and 43 controls.. Body mass index (BMI), serum leptin, and HbA1C were measured in patients and controls; and CSF hypocretin 1 and leptin measured in all patients. Female and male patients with narcolepsy and hypocretin deficiency had the highest mean BMI (27.8 and 26.2, respectively), not statistically different from patients with narcolepsy and normal hypocretin or controls, but statistically higher than the patients with idiopathic hypersomnia (p < 0.001 and 0.011, respectively). The number of obese patients (BMI > 30) was increased in both narcolepsy groups. Serum and CSF leptin levels correlated positively to BMI in patients and controls, but not to CSF hypocretin concentrations. HbA1C was within normal levels and similar in all groups.. The study confirms a moderate tendency to obesity (BMI > 30) and overweight in patients with narcolepsy and cataplexy. Obesity was not correlated to hypocretin deficiency or reduced serum or CSF leptin concentrations. We suggest that overweight and possible metabolic changes previously reported in narcolepsy, may be caused by other mechanisms.

Topics: Adult; Aged; Body Mass Index; Case-Control Studies; Cataplexy; Causality; Comorbidity; Female; Humans; Idiopathic Hypersomnia; Intracellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Middle Aged; Narcolepsy; Neuropeptides; Obesity; Orexins; Overweight; Prognosis; Reference Values; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric

Narcolepsy is a severe sleep disorder that in most patients is characterized by the deficiency of central orexin. Clinically, narcolepsy is associated with obesity. Currently, there is a literature controversy about the potential alteration of leptin levels in narcoleptic patients. Theoretically, diminished leptin levels could partially contribute to the observed overweight of patients. Two studies have reported decreased leptin levels, whereas a larger, recent study failed to detect differences between patients and controls.. To help settle the controversy, we have measured peripheral leptin levels in 42 narcoleptic patients and in 31 body mass index-matched controls.. No significant differences in leptin levels between the groups were observed. Mean leptin levels were 16.0 +/- 14.9 ng/mL in the narcoleptic men and 30.4 +/- 17.8 ng/mL in the narcoleptic women. The corresponding values for the controls were 21.2 +/- 17.0 ng/mL (P = 0.49, men) and 33.9 +/- 16.9 ng/mL (P = 0.31, women). In addition, no correlation was found between leptin levels and clinical symptomatology in the narcoleptic patients.. Taken together, the data argue against a major deterioration of leptin secretion in narcoleptic patients.

Topics: Adult; Aged; Body Mass Index; Female; Humans; Leptin; Male; Middle Aged; Narcolepsy; Reference Values

Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.

Topics: Animals; Female; Intracellular Signaling Peptides and Proteins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Animal; Narcolepsy; Neuropeptides; Obesity; Orexins; Sex Factors; Signal Transduction; Weight Gain

To determine if hypocretin deficiency is associated with abnormally low serum leptin levels, a putative cause of increased body mass index in narcoleptics.. Cross-sectional controlled study.. Three hundred seventy subjects, including 111 healthy controls, 93 narcoleptic subjects with hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 levels < 110 pg/mL), 72 narcoleptic subjects with normal hypocretin levels, and 89 subjects with other sleep disorders. After completing the Stanford Sleepiness Inventory, participants underwent spinal taps and blood sampling for measurement of CSF leptin and hypocretin-1 levels, HLA DQB1*0602 phenotyping, and serum leptin and C-reactive protein levels.. Serum leptin levels were similar in narcoleptic subjects, whether hypocretin-deficient (13.2 +/- 1.7 ng/mL, mean +/- SEM) or not (13.0 +/- 1.8 ng/mL), controls (10.1 +/- 1.1 ng/mL) and subjects with other sleep disorders (11.5 +/- 1.6 ng/mL). Similarly, the CSF leptin levels and the CSF: serum leptin ratios (an indicator of brain leptin uptake) were not different between groups. Serum and CSF leptin levels were higher in women and in subjects with higher body mass indexes. Leptin brain uptake decreased in women, in the aged, and in more-obese subjects. In contrast with a presumed inhibitory effect of leptin on hypocretin-containing cells, CSF leptin levels tended to correlate positively with CSF hypocretin-1 levels. C-reactive protein was higher (4.2 +/- 0.9 mg/L) in narcoleptic subjects with hypocretin deficiency than in controls (1.4 +/- 0.3 mg/L, p = .0055), a difference still significant after adjustment on confounding factors.. Our data do not support a role for leptin in mediating increased body mass index in narcolepsy. A moderate but selective increase in C-reactive protein in hypocretin-1 deficient subjects should prompt research on inflammation in narcolepsy.

Topics: Adult; Blood-Brain Barrier; Body Mass Index; Brain; C-Reactive Protein; Cross-Sectional Studies; Female; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Leptin; Male; Middle Aged; Narcolepsy; Obesity; Orexin Receptors; Phenotype; Receptors, G-Protein-Coupled; Receptors, Leptin; Receptors, Neuropeptide; Reference Values; Sex Factors; Sleep Wake Disorders

While there have been anecdotal observations of binge eating in childhood-onset narcolepsy, the possible relationship between increased weight gain and childhood-onset narcolepsy has not been evaluated.. A retrospective, case-control design was used to compare the body mass index (BMI) of 31 narcolepsy children at the time of diagnosis with that of healthy, age- and gender-matched controls.. The median BMI in the narcolepsy subjects was 22.93 as compared to that in controls of 20.36 (P=0.001). BMI did not differ significantly between narcolepsy subjects who had received prior psychotropic medications and those who had not. The mean BMI of 22 of 31 narcolepsy subjects who had not received psychotropic medications prior to diagnosis was also significantly higher than that of controls (25.1, SEM 1.53 versus 21.1, SEM 0.56; P=0.008 ).. The tendency for increased weight gain is intrinsic to childhood narcolepsy and is manifested relatively early in the course of the disorder. Correlation of this finding with hypocretin and leptin metabolism may further understanding of the pathogenesis of narcolepsy.

Topics: Adolescent; Body Mass Index; Carrier Proteins; Case-Control Studies; Child; Female; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Narcolepsy; Neuropeptides; Obesity; Orexins; Psychotropic Drugs; Retrospective Studies

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 microg/liter in narcolepsy vs. 11.4 microg/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.

Topics: Adult; Carrier Proteins; Circadian Rhythm; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Narcolepsy; Neuropeptides; Orexins; Reference Values

Recently, hypocretins have been implicated in the pathophysiology of narcolepsy, a sleep disorder characterized particularly by the occurrence of excessive daytime sleepiness and cataplexy. Hypocretins, which stimulate food intake, have been reported to be absent in the cerebrospinal fluid (CSF) of the majority of patients suffering from narcolepsy. Because these patients also display an increased body mass index (BMI), it has been suggested that disturbances in metabolism and food intake regulation may be present. To further investigate these presumed alterations, we studied the production of leptin, a fat-cell-derived hormone signaling to the brain the size of the adipose tissue. We measured the levels of leptin in serum and CSF from 15 narcoleptic patients and compared the results to those from age-, sex- and BMI-matched control groups of depressive patients and patients suffering from a noninflammatory neurological disorder. Compared to both control groups, leptin levels in serum, but not in the CSF, were significantly reduced in narcoleptic patients by more than 50%. These results support the hypothesis that human narcolepsy is accompanied by complex alterations of the regulation of food intake and metabolism. The significance of these alterations for the core symptomatology of narcolepsy should be a target of future research.

Topics: Depressive Disorder, Major; Humans; Leptin; Narcolepsy; Nervous System Diseases; Osmolar Concentration; Reference Values