From preclinical models to clinical efficacy Free

The paper entitled “Leptin-mediated neural targets in obesity hypoventilation syndrome” [1] provides an incisive review linking sleep disorders medicine and sleep neurobiology. Specifically, this paper reviews evidence that leptin resistance contributes to the depressed hypercapnic ventilatory response that is characteristic of obesity hypoventilation syndrome. The satiety factor leptin, a product of adipocytes, is regulated by the ob gene, first cloned in 1994 for mouse and human [2]. Remarkably, the discovery that the ob gene and leptin modulate food intake and body weight were made 6 years before the initial sequencing of the mouse genome [3]. The homology between mouse and human genome led the NIH to opine that mouse provides “the premier mammalian model system for genetic research” [4]. Five years later the Nobel Prize was awarded for research using Drosophila that discovered the genetic basis of circadian rhythms [5]. Thus, research across clades that combine genetics, systems physiology, and behavior is empowered to promote discoveries that make a lasting contribution to the transdisciplinary, one health concept [6].

The Amorim et al., review [1] highlights the progress that has come from an active exchange between basic research using mice and studies of normal weight and obese humans. Evidence of the exciting scientific exchange between clinical and preclinical studies of leptin is provided by literature searches using Semantic Scholar. Searches from 1994 to 2022 returned 6 350 000 citations for “leptin reviews,” 564 citations for “leptin and breathing,” and 719 citations for “leptin signaling in the central nervous system.” Incidentally, Semantic Scholar lists work by coauthors of the Amorim et al., review among the 100 most influential papers on leptin and breathing. These numbers, and data from ProQuest documenting about 17 000 PhD dissertations related to leptin, support the selection of Amorim et al., for an editorial focus. The review [1] also anticipates the fact that 2024 will mark the third decade since the discovery that leptinergic transmission suppresses appetite and regulates metabolism [2]. Figure 1 visualizes the persisting impact of the 1994 Zhang et al., discovery [2] for ongoing leptin research.

Figure 1.

This network diagram illustrates how the 1994 Zhang et al. report on cloning of the obese [2] gene is connected to contemporary reports on leptin. The circular nodes represent publications subsequent to Zhang et al., and the sizes of the nodes reflect log₂ number of citations of the publications. The edges connect related publications which are identified by first author name and year of publication. The Zhang et al. paper was entered as the network stem. Figure was produced using https://www.litmaps.com/.

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The nine subsections of this carefully curated review [1] are appealingly didactic. The authors synthesize a large body of literature using both inductive and deductive approaches. The review is an ideal resource for teaching a range of topics to learners at many levels. The discovery that the circulating hormone leptin modulates many aspects of physiology and behavior recapitulates pioneering studies of sleep. Early studies hypothesized that some sleep-promoting chemical accumulated during prolonged wakefulness. This led to many experiments involving parabiosis or cross perfusion of cerebrospinal fluid from sleep-deprived animals into animals without sleep deprivation. For an excellent historical review of such studies, see [7]. The glucostatic theory of energy regulation [8] is another relevant example of a blood born molecule regulating the complex behavior of feeding. Today we have the advantage of a unifying hypothesis that complex behaviors like sleep, feeding, and breathing are initiated and regulated via chemical transmission in the peripheral and central nervous system.

The review [1] shows that leptin levels and/or leptin receptors, localized to specific neuronal networks, have the potential to serve as targets for therapeutic intervention. The very elegant and difficult preclinical studies in murine models, performed by the authors of the review, have demonstrated that leptin, administered in specific regions of the medulla, known for their role in generating or controlling breathing, as well as systemically, do stimulate breathing in overfed obese mice or in animals genetically deficient in leptin (ob/ob mice), a rare genetic defect in humans. In addition, chemosensitivity can be clearly improved by leptin, while the authors bring convincing data to support the view that leptin decreases the susceptibility of upper airway collapse during inspiration. As discussed by the authors in their insightful review [1], the framework currently used to understand and treat obesity hypoventilation and OSA in patients remains debated. The mechanisms leading to these potentially life-threatening breathing control abnormalities are still not fully understood [9]. These mechanisms may not be limited to specific alterations of the chemoreception or feedback control mechanisms, including disturbances in metabolism, which in small-sized animals can offset the effects of hypoxia for instance, a response that is not present in larger mammals [10]. “Elementary” effects of leptin on specific medullary neural networks involved in breathing control are extremely encouraging [1]. The extent to which such models intended to mimic sleep disordered breathing will be transferable from mice to obese, as well as nonobese, humans will need to pass the test of “clinical efficacy in human studies.”

Therefore, the logical next step of this fascinating research, as discussed in the last paragraph of the review, is to determine whether administration of leptin—or leptin analogues—to patients with obesity hypoventilation syndrome and/or OSA can restore arterial blood gas homeostasis. It means showing, in groups of obese patients, that leptin increases alveolar ventilation during sleep and when awake, while decreasing the number and/or magnitude of OSA. The challenge is at the level of the expectations! The adherence to the current treatments of obesity hypoventilation syndrome remains problematic: weight loss is not always achievable, while the acceptability of noninvasive pressure support, a very effective approach [11], remains limited [12]. Limitations are also present for treating OSA; a low adherence to nocturnal continuous positive airway pressure (CPAP) often requires alternative therapies [13]. These include oral appliances for which higher acceptance may compensate for a lower rate of reduction of OSA than CPAP. Unilateral stimulation of the hypoglossal nerve can lead to ~70% reduction in OSA severity [13]. It remains an invasive approach, with a high cost and still limited indications in obesity. Exercises involving the tongue and the pharyngeal muscles can improve OSA but again with a lower efficacy than CPAP, while nasal EPAP can reduce OSA severity by ~50% only in the general population of OSA [13]. These approaches with their respective levels of efficacy and acceptance rate do not always provide a satisfactory solution for treating obesity hypoventilation and OSA in all patients.

The search for a medication able to increase breathing in obese patients, i.e., restoring alveolar ventilation while recovering a proper dynamic of the upper airways when asleep, is certainly the holy grail of sleep medicine. Leptin is not the first hormone proposed for this indication; progestogen for example was previously shown to exhibit efficacy in obesity hypoventilation syndrome [14], but its many side effects have limited its use.

Clinical studies on leptin efficacy are therefore timely. They will be much easier to perform than in the past since we have access to a new molecule, a recombinant human leptin (Metreleptin) that is already FDA approved for other indications. An extension of label/repurposing could be rapidly achieved, if proven effective. Finally, the use of the intra-nasal route is very attractive as a suitable alternative to subcutaneous injections.

A series of fundamental questions will need to be addressed when designing appropriate clinical studies: The dose of leptin to be used is certainly one of them. The FDA has developed recommendations [15], based on allometric relationship, regarding how to translate doses used in mice to humans. However, this topic is still debated in the literature [16, 17]. There is no simple way to predict, without preliminary trials in humans, whether the allometric relations between dose and body surface is applicable to leptin. In addition, obesity in humans is marked by a resistance to leptin [18], so dose-response curves may differ from those in control subjects and will need to be established in these patients as well. Other important questions remain to be answered: The long-term effects on breathing stability and upper airway resistance of chronic administration of leptin will need to be determined, along with potential tachyphylaxis, side effects and toxicity. Is leptin to be used alone or in combination with other treatments, including noninvasive ventilation, reducing in turn the need for high pressure support, a reason for poor acceptability? Will leptin be effective in other abnormalities of breathing control in humans, such as congenital primary hypoventilation, for instance, or drug-induced ventilatory depression? And if it is, at what dosage?

Since the description of the first therapeutic approach (~300 BC) offered to Dionysius, the tyrant of Heracleia, who suffered from morbid obesity, and who was prescribed to be thoroughly pocked and pierced by long needles, in a repetitive manner, when asleep to prevent him from “choking himself to death,” [19] less aggressive approaches have been offered [11]. Unfortunately, many of the current treatments remain cumbersome or poorly accepted by too many patients. When weight loss is not achievable, access to simple and nontoxic medications, such as leptin, could represent the next fundamental stage of the treatment of the deleterious and still mysterious alterations in breathing control produced by obesity. An exciting field of experimentation is in front of us.

Disclosure Statement

None declared.

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