In a recent review published in the Nutrients Journal, researchers examined the current evidence of the intricate relationship between orexin, rapid eye movement (REM) sleep, and appetite.

Study: Rethinking the Role of Orexin in the Regulation of REM Sleep and Appetite. Image Credit: Olena Yakobchuk/Shutterstock.com

Background

They discussed their interconnectedness in physiological and diseased states, such as sleep-related eating disorders (SRED), night eating syndrome, idiopathic hypersomnia, and narcolepsy, insights into which could help unravel the complex mechanisms underlying sleep-wake patterns and metabolic control.

Introduction

Orexin, or hypocretin, is a neurotransmitter comprising two similar peptides, orexin A and B, which act through different receptors.

It is primarily synthesized in the lateral hypothalamus and is well-recognized to inhibit REM sleep and promote wakefulness, but the latter to a lesser extent; additionally, orexin regulates feeding behavior.

Other orexin functions encompass autonomic nervous system regulation, cognitive function modulation, and energy homeostasis. 

Orexinergic pathways are involved in autonomic nervous system imbalances. They contribute to the activation of the stress response associated with cardiovascular disorders. Orexin also affects several cognitive functions, including arousal, attention, learning, and memory. 

Furthermore, orexin interacts with various metabolic centers in the brain, manages energy expenditure, thermogenesis, and lipid metabolism, and, thus, helps maintain energy homeostasis.

Thus, dysregulation of orexin-producing neurons could lead to metabolic disorders. e.g., diabetes, by promoting food-seeking behavior and stimulating food intake. Orexin also interacts with leptin, a hormone regulating satiety and energy expenditure, to regulate feeding behavior and energy homeostasis. Similarly, it interacts with insulin-producing pancreatic beta cells to affect glucose homeostasis.

Role of Orexin in REM Sleep and appetite regulation

REM sleep is a complex physiological process with several functions, such as information processing, neural transmission modulation, memory consolidation, regulation of feeding behavior, body temperature, and stress response, to name a few.

Studies have demonstrated the distinctive roles of cholinergic and glutamatergic neurons in REM sleep regulation.

The former gets activated with fast cortical rhythms and during wakefulness, while the latter fires during REM sleep and wakefulness. A third type of neurons, GABAergic neurons, also help regulate REM sleep.

Studies have also shown that orexin levels are highest immediately after sleep onset, decline throughout the night, and rise again after waking. In other words, orexin levels in the body do not promote alertness but inhibit REM sleep. 

Patients with narcolepsy type 1 experience episodes of REM sleep during wakefulness or early after falling asleep due to a decreased orexin activity. Thus, orexin receptor antagonists, which block the action of orexin, help them sleep longer and improve their sleep continuity. 

Studies have shown how these medications enhance REM sleep regulation and improve other sleep parameters, including total sleep time and reduced sleep latency.

REM sleep is most abundant towards the last hours of night sleep and acts as an appetite suppressant. Moreover, REM sleep influences people's food preferences and dislikes.

Individuals with narcolepsy might be hypophagic, i.e., they have suppressed food ingestion. Yet, due to disruptions in their orexin system, they might consume more food and gain weight.

Some narcolepsy patients also have SRED, characterized by sleep feeding. Orexin receptor agonists might help manage SRED by modulating orexin signaling. 

Furthermore, the circadian trend of orexin influences appetite. Thus, patients with night eating syndrome experience longer feeding episodes and delayed sleep onset in the evening when their orexin levels are low.

Furthermore, orexin interacts with neuropeptide Y and melanin-concentrating hormone to regulate appetite. 

Given its neuroprotective properties, orexin could also be a potential target for therapeutic interventions aimed at correcting feeding disturbances in neurodegenerative diseases, such as Parkinson's, Alzheimer's, and Huntington's disease.

However, more research is needed to fully understand the interactions of orexin with REM sleep and appetite to develop safe and effective therapies.

Conclusions

Given the crucial role orexin plays in regulating REM sleep and appetite, further research should aim to develop novel therapies for sleep disorders and metabolic conditions associated with orexin dysregulation.

Orexin receptor agonists have obvious use in narcolepsy and insomnia treatment; however, several other disorders might benefit from a pharmacological agent targeting orexin. 

For example, studies have shown that orexin receptor antagonists could help reduce drug-seeking behavior, suggesting their use as adjunct treatments for addiction because orexin neurons modulate the dopaminergic system.

Further studies should test drug candidates acting on orexinergic circuits, which could treat anxiety and post-traumatic stress disorder (PTSD), also often associated with eating disorders. 

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.