A Systems-Based Hypothesis for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Phosphatidylcholine Deficiency, Insulin Signaling and Noradrenergic Neuron Dysregulation

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease characterised by profound fatigue, post-exertional malaise, and multi-systemic dysfunction. This hypothesis proposes that ME/CFS results from noradrenergic neuron dysfunction due to increased neuronal insulin receptor sensitivity, potentially caused by glucocorticoid receptor resistance, high insulin levels, and insulin receptor gene variants. An additional contributing factor is phosphatidylcholine deficiency, which may exacerbate neuronal insulin hypersensitivity and disrupt cellular function. We explore genetic, metabolic, and inflammatory factors that contribute to phosphatidylcholine deficiency and propose a multi-component model of ME/CFS, highlighting the interplay between phosphatidylcholine metabolism, liver dysfunction, neuronal function and inflammatory signaling. Furthermore, we discuss how dysregulated norepinephrine signaling impacts various brain regions and peripheral systems, contributing to the wide-ranging symptomatology of ME/CFS.