A recent review highlighted the devastating multi-system effects of COVID on the body, particularly emphasising the endocrinological (hormonal) consequences manifesting in long COVID, and additionally ME/CFS in a proportion of people. The review honed in on the potential influences of chemical messenger orexin and glucagon-like peptide-1 (GLP-1) “another key player in metabolism”.
Why Orexin?
Orexins are neuropeptides (chemical messengers produced in a part of the brain called the hypothalamus) that “play a crucial role in the regulation of the sleep-wake cycle, food intake, energy homeostasis, the autonomic nervous system, and stress responses”.
According to the authors, disorders of the orexin system closely resemble long COVID (with or without ME/CFS), therefore it is worth investigating whether orexin is involved in the pathophysiology of long COVID. The overlap in characteristics noted include fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, which they suggest supports a mechanistic model in which impaired orexin signalling “contributes to postviral endocrine and metabolic dysfunction.” However, this remains a bold hypothesis, given that long COVID and ME/CFS share symptoms with many other conditions.
Why GLP-1?
GLP-1 is a natural hormone produced in your gut that regulates appetite, blood sugar, and the feeling of fullness. Drugs targeting GLP-1 receptors (GLP-1 receptor agonists) are currently a hot topic in ME/CFS-related news due to discussion of their effects beyond their established use in diabetes and obesity management. The review notes that whilst these drugs are used to treat metabolic diseases (such as the aforementioned), they increasingly are also shown to have “a general anti-inflammatory effect and a positive effect on the cardiovascular system”.
Relevance and therapeutic potential
The authors suggest that therapeutic interventions targeting orexin and GLP-1 pathways represent promising avenues to counteract the neuroendocrine and metabolic disturbances found in long COVID.
Supporting Evidence?
Orexin
Unfortunately, much of the evidence relating to Orexin in the review is taken from animal studies (rodents) and support the idea that disrupting orexin signalling can result in symptoms similar to long COVID, hence establishing the feasibility of the link rather than direct confirmation in humans. The paper describes evidence from rodent models about what happens when orexin is disrupted, including stress response differences, metabolic changes, and respiratory issues. Human data remains suggestive and observational – primarily based on symptom correlation and the “natural experiment” of narcolepsy (sleep-wake disorder) patients. There is currently an absence of large-scale clinical trials directly proving orexin deficiency as a primary driver of ME/CFS.
Interconnectivity with GLP-1s
The authors present GLP-1 receptor agonists as having influences on immunity, inflammation, and neuroprotection. GLP-1 neurons project to areas of the hypothalamus where orexin neurons are located, and experiments with GLP-1 receptor agonists in mice indicate that orexin neurons express GLP-1 receptors. Furthermore, orexin neurons project to areas of the brainstem involved in GLP-1 production, suggesting “bidirectional interaction” between GLP-1 and orexin pathways. Caveat: The authors acknowledge again much of the data on the interaction between the systems “comes from animal models and the transferability to humans still needs to be further investigated.”
The review also notes that sex differences are a prominent feature in long COVID and sex differences in the response to GLP-1 receptor agonists and the orexin system can be noted
Future therapeutics
The authors posit that COVID infection leads to increased gut permeability (leaky gut), and that in rats – GLP-1 receptor agonists and orexin can preserve the integrity of the intestinal barrier, so there is potential therapeutic benefit. In fact, the authors propose investigating the use of a range of drugs that modulate the orexin system and GLP-1 receptor agonists to stabilise the symptoms and potential underlying disease mechanisms of long COVID and ME/CFS. Interestingly, the review highlights that the sex of an individual may influence responses to both GLP-1RAs and orexin-based therapies, an area that must be addressed in future research.
There are many methodological limitations, which the review itself acknowledges, these include:
- Current insights into the orexin (OX) system and GLP-1 interactions are largely based on animal models
- Long COVID and ME/CFS are highly heterogeneous and dynamic, “which complicate both clinical assessment and biomarker development”
- Individuals with severe symptoms, “a group whose data would likely be the most informative”, are frequently unable to participate in trials due to post-exertional malaise, and invasive procedures raise ethical concerns
- Existing studies are often limited by issues such as small sample sizes, lack of standardised diagnostic criteria, and a failure to take into account sex-based differences
Conclusion
Whilst the Orexin and GLP-1 systems contribute to a compelling hypothesis for understanding the multisystemic nature of long COVID and ME/CFS, it is vital to remember that current evidence only suggests potential mechanisms rather than confirming them as direct causes. We can only infer links at this stage, therefore, further work is needed to move beyond theoretical models.
