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

Abstract

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).