BRIDGING METABOLISM AND PAIN: TRANSCRIPTOMIC EVIDENCE FOR A KEY ROLE OF SPINAL OLIGODENDROCYTES

Chronic pain affects approximately 20% of adults and is disproportionately prevalent in metabolic disorders. Over ⅓ of individuals with obesity or diabetes experience chronic pain, while impaired glucose tolerance is associated with increased neuropathic pain risk even in non-diabetics. In rodent models, consumption of a Western Diet (WD) induces pain-like behaviors, as does selective depletion of oligodendrocytes (OLs), suggesting a mechanistic link between metabolic state, myelin integrity and sensory processing. To investigate this link, we used a WD to induce metabolic imbalance and mechanical hypersensitivity in a transgenic mouse model and performed single-nucleus RNA sequencing (snRNAseq) of the spinal cord after three months of diet exposure. WD-fed mice segregated into two phenotypes: animals with normal mechanical sensitivity, comparable to regular-diet controls, and animals exhibiting prolonged hypersensitivity. Transcriptomic analysis revealed that OL lineage cells constitute over 47% of spinal cord nuclei and are among the most diet-responsive populations. WD exposure was associated with downregulation of oxidative phosphorylation-related transcripts, while pain-susceptible animals showed additional suppression of myelin genes (Mbp, Mag, Mog, Cnp, Plp1) and mRNA processing pathways. Moreover, WD and pain differently altered predicted intercellular communication within the spinal cord. Together, these findings position spinal OLs as central integrators of metabolic and sensory signals, suggesting that OL dysfunction and myelin disruption may underlie the increased pain vulnerability associated with metabolic imbalance.