Preprint A Systems-Based Hypothesis for ME/CFS: Phosphatidylcholine Deficiency, Insulin Signaling and Noradrenergic Neuron Dysregulation, 2025, Tamara Carnac

[Sly Saint]

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

Tamara Carnac

pre-print

Abstract
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.

https://www.preprints.org/manuscript/202409.1467/v2

 

[Yann04]

I’m too foggy to understand anything but this looks interesting I think?

Somewhat sceptical of the strong claims made here:

Mast cell activation syndrome (MCAS) has been implicated in the pathophysiology of ME/CFS,
with evidence suggesting it may act as both a primary driver of disease and a secondary consequence
of other dysregulated pathways. In certain patients, MCAS could serve as a root cause by promoting
metabolic and inflammatory disturbances that contribute to disease onset. One proposed mechanism
involves the protease tryptase, a mast cell-derived enzyme that has been shown to influence hepatic
lipid metabolism. Tryptase can activate protease-activated receptors (PARs) in hepatocytes,
to up-regulation of sterol regulatory element-binding protein 1 (SREBP-1) and increased lipogenesis.
Additionally, mast cell-derived histamine and tryptase can activate phospholipase A2 (PLA2) and
cyclooxygenase-2 (COX-2), increasing the breakdown of cell membrane phospholipids, including PC.
Conversely, in other patients, MCAS may emerge as a downstream effect of autonomic and
immune dysregulation. In this paper it has been suggested that sustained high levels of
norepinephrine can lead to the downregulation of β₂-adrenergic receptors (β₂-ARs). If this
downregulation happens to mast cell β₂-ARs, this could lead to increased mast cell reactivity. This
effect may be further exacerbated by glucocorticoid receptor resistance in mast cells. Since functional
glucocorticoid receptors are required for mast cell stabilisation, resistance to glucocorticoid signaling
could result in an uninhibited mast cell response, perpetuating a hyperinflammatory state. This
creates a vicious cycle in which MCAS exacerbates phospholipid depletion, inflammation, and
metabolic dysfunction, feeding back into the pathological mechanisms of ME/CFS.
Regardless of whether MCAS serves as a primary trigger or a secondary consequence, its
contribution to systemic inflammation, membrane lipid dysregulation, and microcirculatory
impairment suggests that targeting mast cell activation may be a critical therapeutic strategy. Even
in cases where MCAS is a downstream effect, its ability to amplify disease pathology warrants clinical
intervention to break the cycle of inflammation and metabolic dysfunction

 

[Jonathan Edwards]

Yes, I think there are a number of interesting threads in this hypothesis. And I agree that bringing in MCAS does not help.

Some of these things like phospholipids and insulin resistance looks if they may be implicated in ME/CFS despite no very obvious reason why they should. My main concern about the mode, as formats metabolic approaches, is the lack of a clear explanation for onset and 'disease memory'. The adaptive immune system provides neat ways to handle those but basic metabolic pathways should just go on being the same unless we have some 'learned epigenetic' input to skew the regulation long term.

 

[rapidboson]

Prefacing with the comment that I've only let the hypotheses be summarized by AI, I have not been able to read the paper yet.

From what I understand, the main idea is NET expression reduction (due to or exacerbated by increased insulin receptor sensitivity, potentially caused by PC deficiency), leading to elevated extracellular NE which then downstream causes a bunch of problems either directly or indirectly?
One of the downstream problems being desensitization/downregulation of beta 2 receptors (not a new concept -> also part of Wirth/Scheibenbogen hypothesis, though in their work AAb induced)?

Could this not be tested quite pragmatically with a2R agonists (reduce NE release), b2R antagonists (re-sensitize b2R over time), ketogenic diet (reduce insulin levels?), cox-2 inhibitors (preserve PC)?

 

[TamaraRC]

I made a video for the second part of the hypothesis (the part focusing on phosphatidylcholine), it might be easier than reading through the paper.