Lysophosphatidylcholine induces heat pain hypersensitivity in obese mice fed with a high-fat diet through activation of peripheral Acid-Sensing Ion Channel 3

Diet induced obesity is one of the major causes of obesity, which affects 13% of the world’s adult population. Obesity is correlated to chronic pain regardless of other components of the metabolic syndrome. Our study focuses on investigating the effect of high-fat diet induced obesity on peripheral sensory neurons activity and pain perception, followed by deciphering the underlying cellular and molecular mechanisms that involve Acid-Sensing Ion Channel 3 (ASIC3). We show here that heat sensitive C-fibers from mice made obese by consumption of a high-fat diet exhibited an increased activity during baseline and upon heating. Obese mice showed long-lasting heat pain hypersensitivity once obesity was well established, while mechanical sensitivity was not affected. We found that the serum of obese mice was enriched in lysophosphatidylcholine (LPC) species (LPC16:0, LPC18:0 and LPC18:1), which activate ASIC3 channels and increased peripheral neuron excitability. Genetic deletion and in vivo pharmacological inhibition of ASIC3 protected and rescued mice from obesity-induced thermal hypersensitivity. Our results identify ASIC3 channels in DRG neurons and circulating LPC species that activate them as a mechanism contributing to heat pain hypersensitivity associated with high-fat diet induced obesity. ### Competing Interest Statement The authors have declared no competing interest.