Postviral syndromes are heterogeneous, multisystem disorders that develop following acute viral infections. During the COVID-19 pandemic, there was a marked increase in patients with persistent symptoms after infection with SARS-CoV-2, collectively referred to as postacute sequelae of COVID-19 (PASC). Many individuals meeting PASC definitions also fulfill criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of postviral disease. Core clinical features of ME/CFS include profound fatigue, postexertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and dysregulation of autonomic and immune systems. This review synthesizes evidence that two neuroendocrine–metabolic regulators, orexin (OX) and glucagon-like peptide-1 (GLP-1), may play central roles in the pathophysiology and potential treatment of postviral syndromes.
Orexin neuropeptides are produced centrally and are established regulators of arousal, energy balance, and neuroendocrine function. Dysfunction of the OX system produces phenotypes that overlap with cardinal symptoms of PASC and ME/CFS, including fatigue and sleep disturbances. The review positions impaired orexin signaling as a plausible mechanistic link connecting stress responses, immune activation, and downstream metabolic alterations observed in postviral conditions. The source emphasizes the conceptual role of orexin as a central integrator of behavioral and physiological states relevant to postviral disease presentations.
A principal focus of the review is the role of OX in regulating peripheral and central aspects of metabolism. Orexin signaling influences glucose metabolism and interacts with hypothalamic–pituitary–adrenal (HPA) axis activity. These pathways are relevant because metabolic dysfunction, including impaired glucose handling and insulin resistance, is reported in postviral syndromes and intersects with fatigue and cognitive symptoms. The source frames impaired orexin activity as a contributor to postviral endocrine and metabolic dysfunction through effects on glucose regulation and HPA axis modulation. Specific mechanistic details, experimental measures, or quantitative outcomes beyond this conceptual link were not reported in the abstracted source text.
The review highlights sexually dimorphic expression and function of the orexin system, suggesting that sex-specific differences in orexin biology may influence susceptibility, symptom expression, or course of postviral syndromes. This aspect is raised in the context of understanding heterogeneity across patient populations with PASC and ME/CFS. The abstract does not provide detailed data on magnitude or clinical correlates of these sex differences; it indicates the topic as an important consideration when evaluating orexin-related mechanisms in postviral conditions.
Glucagon-like peptide-1 (GLP-1) is discussed as another central regulator of metabolism with broader actions that may be relevant to postviral disease. Beyond glycemic control, GLP-1 is described as having neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. These pleiotropic functions provide a rationale for considering GLP-1 pathways when examining the persistent multisystem manifestations of PASC and ME/CFS, particularly where metabolic and inflammatory processes overlap. The abstract does not present trial-level evidence but frames GLP-1 as a biologically relevant mediator in an integrated disease model.
The review emphasizes emerging therapeutic strategies that target the GLP-1 system (notably GLP-1 receptor agonists, GLP-1RAs) and pharmacologic modulation of the orexin system. These approaches are presented as promising avenues to address neuroendocrine and metabolic dysfunction in PASC, ME/CFS, and other postviral syndromes. The abstract notes these strategies conceptually but does not report specific clinical trial results, safety profiles, or dosing regimens within the provided text.
Bringing together the roles of OX and GLP-1, the review proposes an integrated framework in which dysregulated neuropeptide signaling contributes to systemic homeostatic disturbances observed after viral infections. This model links central regulators of arousal, metabolism, and immune function to the clinical phenotype of prolonged fatigue, sleep disturbance, metabolic impairment, and neuropsychiatric symptoms that characterize many cases of PASC and ME/CFS. The framework is intended to support mechanistic understanding and to inform development of targeted interventions.
The source concludes that orexin and GLP-1 systems are key neuroendocrine–metabolic players in postviral syndromes and that their dysfunction offers a coherent explanatory model for many clinical features of PASC and ME/CFS. The review highlights sexually dimorphic orexin biology and proposes therapeutic exploration of GLP-1RAs and orexin-targeting drugs. The abstracted material does not include detailed experimental results, specific clinical trial outcomes, or practical treatment recommendations; such details were not reported in the provided source text.