Activating Leptin Receptors in the Central Nervous System Using Intranasal Leptin. A Novel Therapeutic Target for Sleep-disordered Breathing

In addition to serving as a tissue for energy storage, adipose tissue has become a well-recognized endocrine organ that secretes a variety of adipokines with important pleiotropic functions. One of these adipokines is leptin, discovered in 1994 by Zhang and colleagues (1). Much of the research on leptin has focused on its role on metabolism, particularly in central nervous system regulation of energy homeostasis and obesity, as well as its peripheral effects on obesity-related cardiometabolic diseases. The excess adiposity in obese humans leads to high circulating levels of leptin. Paradoxically, despite leptin’s well-described effects on suppressing appetite and increasing energy expenditure, these individuals remain obese, reflecting a state of leptin resistance (2). A few years after its discovery, it became evident that leptin has a significant effect on ventilation and control of breathing (3, 4). At the central nervous system level, leptin increases the hypercapnic ventilatory response. Yet, severely obese patients afflicted with obesity hypoventilation syndrome (OHS) continue to hypoventilate despite having high circulating levels of leptin, in line with leptin resistance. Further evidence in support of leptin resistance at the central nervous system level comes from experiments in which parenterally administered recombinant leptin was shown to be largely ineffective in reducing weight in the vast majority of obese individuals (5). For leptin to affect the respiratory center and increase minute ventilation, it has to first cross the blood–brain barrier (BBB). One proposed mechanism for leptin resistance is impaired leptin transport across the BBB (6).

Against this background, in this issue of the Journal, Berger and colleagues (pp. 773–783) postulated that intranasal administration of leptin could bypass the BBB and thus promote its physiologic action on the control of respiration and the upper airway, consequently mitigating sleep-disordered breathing (SDB) (7). The finding that intranasal leptin can alleviate hypoventilation and upper-airway obstruction in an obese mice model is exciting because it provides a much-needed novel therapeutic approach for the management of SDB. Since its introduction in 1981, positive airway pressure (PAP) therapy has remained the gold standard treatment for SDB (8). However, despite its high effectiveness, PAP therapy has low clinical efficacy, primarily due to suboptimal adherence in a large proportion of patients (9). Moreover, approximately 25% of patients with OHS remain hypercapnic despite high levels of adherence to nocturnal PAP therapy (10). As such, it is not surprising that there has been much interest in discovering novel therapeutic targets and modalities (11–13). Any therapy that is able to effectively maintain upper-airway patency and normalize ventilation throughout the entire sleep period will go a long way toward improving long-term health outcomes in patients with SDB, and will be a welcome addition to our armamentarium to treat disordered breathing during sleep. One concern regarding ventilatory stimulants is exposing the upper airway to increasingly negative intrathoracic pressure, thereby promoting upper-airway collapse. However, Berger and colleagues demonstrated that intranasal leptin improves inspiratory flow limitation despite its ventilatory stimulant effect (7). This finding, in conjunction with transneuronal tracer experiments, suggests that at the central nervous system level, leptin can simultaneously improve ventilatory response and upper-airway tone through synaptic connections between leptin receptor–expressing cells and hypoglossal and phrenic motor neurons.

Although prior work has explored the effect of intranasal leptin administration on reducing food intake in rats (14, 15), Berger and colleagues provide a very elegant, albeit preliminary, physiological demonstration of how leptin delivered intranasally can overcome “central leptin deficiency” and lead to demonstrable improvement in upper-airway resistance and ventilation in a murine model (7). However, as with any well-designed and novel animal experiment, there are many unanswered questions. First and foremost, the demonstration of an acute effect of intranasal leptin has less clinical relevance for managing a chronic disease such as SDB. Therefore, more research is needed to demonstrate the long-term efficacy of intranasal leptin in alleviating SDB. In theory, if this acute effect is sustained after repeated administrations without significant side effects, the long-term modulation of cerebral areas that control appetite as well as breathing may have further desirable effects on health beyond those of improving SDB and ventilation. Such effects cannot be assumed until the experiments are done and new evidence becomes available. It also remains unclear whether improvement in ventilation during sleep would be sustained during wakefulness to ameliorate daytime hypoventilation, a hallmark of OHS. Second, the exact mechanism by which intranasal leptin exerts its action of relieving SDB needs to be further elucidated. The use of the intranasal route stemmed from its ability to bypass leptin resistance, which is attributed, at least in part, to limited permeability of the BBB to leptin. However, recent work suggests that leptin transport into cerebrospinal fluid is intact in obese mice (16). Although this does not contradict the finding that intranasal leptin, and not intraperitoneal leptin, relieved SDB, it is clear that much more needs to be explored regarding the traffic of leptin into the central nervous system and its mechanisms of actions on various parts of the brain. Prior studies exploring the effect of intranasal leptin on appetite and weight in mice and rats used substantially lower concentrations (0.1 or 0.2 mg/kg) (14, 15) than the current study, in which the delivered dose was 0.4 mg/kg. Whether the dose needs to be adjusted based on the therapeutic goal (i.e., appetite vs. respiratory modulation) also requires further investigation. Lastly, further research is needed to identify the patient population that will be most responsive to this therapeutic modality.

Although we are excited by this novel finding of intranasal leptin in the murine model, the translation to humans cannot be taken on a mere leap of faith, as men are not mice. The sleep medicine community eagerly awaits additional experiments and clinical trials exploring intranasal leptin in the management of SDB.