The novel data on various neuroendocrine axes and body weight of narcoleptic humans presented in this chapter extend our knowledge of narcolepsy and may affect our thinking about the pathophysiology of the disease.
The data on the HPA axis strongly suggest that the master pacemaker dictating circadian timing is intact in narcoleptic patients. The circadian timing of HPA output is generally recognized to be a close reflection of pacemaker activity (52). The timing and amplitude of the acrophase of ACTH and cortisol in plasma were similar in patients and controls. The circa-dian distribution of body temperature fluctuations, another reliable measure of endogenous time keeping by the biological clock (53), is also normal in narcoleptic humans (54), which supports the notion that the master pacemaker is unaffected by the disease. However, the distribution of sleep and wakefulness, which is primarily determined by clock timing, is severely disturbed in narcoleptics. To reconcile these facts, it has been proposed that inputs from the SCN into hypocretin neurons drive clock-dependent alertness in healthy humans and that destruction of these neurons therefore abrogates the impact of an intact master pacemaker on the circadian sleep-wakefulness cycle in narcoleptics (55).
The data summarized in this chapter suggest that hypocretin neurons also link SCN activity with adipocyte leptin secretion, probably via the autonomic nervous system. The impact of hypocretin neurons on the autonomic nervous system may be either direct or indirect through modulation of sleep and wakefulness.
Reduced circulating leptin levels may be involved in the pathogenesis of obesity in nar-coleptic patients. The fact that narcoleptic patients are obese in the face of hypophagia suggests that they spend less energy, which is supported by early observations (2). Leptin is critically involved in the control of energy expenditure, and hypoleptinemia is associated with a lower metabolic rate in obese animal models. Alternatively, hypocretin deficiency may reduce basal metabolism directly via its inhibitory impact on the sympathetic nervous system.
In concert with reports alluded to earlier, the present data are in keeping with the postulate that hypocretin neurons play a role in the control of hypothalamic CRH and GHRH release. Hypocretin deficiency may blunt CRH secretion, which could compromise wakefulness and reduce pituitary ACTH release; disrupted hypocretin control of GHRH release may contribute to the pathogenesis of daytime naps and increased diurnal GH secretion in narcoleptic humans.
It remains to be established whether the neuroendocrine anomalies described here are of clinical significance. At first sight, it is hard to believe that reduced ACTH release in the face of normal circulating cortisol levels, disrupted circadian distribution of GH secretory events that produce normal amounts of GH, reduced circulating TSH levels in the face of normal thyroid hormone concentrations, and diminished circulating leptin concentrations have clinically relevant effects in narcoleptic patients. Also, narcolepsy is not known to be associated with any clinically relevant endocrine anomaly. However, it is important to realize that the hormonal ensembles were not explored in the studies reported to date.
In conclusion, hypocretin neurons may be involved in control of the autonomic nervous system, leptin secretion by adipocytes (via autonomic neural inputs), and hypothalamic CRH and GHRH release, which would explain the various neuroendocrine and metabolic anomalies in narcoleptic humans that are described here.
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