Acid-sensing ion channel 3 mediates pain hypersensitivity associated with high-fat diet consumption in mice

Author:

Negm Ahmed1ORCID,Stobbe Katharina2,Ben Fradj Selma2,Sanchez Clara2,Landra-Willm Arnaud1,Richter Margaux1,Fleuriot Lucile3,Debayle Delphine3,Deval Emmanuel1,Lingueglia Eric1,Rovere Carole2,Noel Jacques1ORCID

Affiliation:

1. Université Côte d'Azur, CNRS, IPMC, LabEx ICST, FHU InovPain, Valbonne, France. Negm is now with the Université Clermont-Auvergne, Laboratoire Neurodol, UMR 1107 Inserm, Clermont-Ferrand, France

2. Université Côte d’Azur, CNRS, IPMC, LabEx SIGNALIFE, Valbonne, France

3. Université Côte d’Azur, CNRS, IPMC, Valbonne, France

Abstract

Abstract Lipid-rich diet is the major cause of obesity, affecting 13% of the worldwide adult population. Obesity is a major risk factor for metabolic syndrome that includes hyperlipidemia and diabetes mellitus. The early phases of metabolic syndrome are often associated with hyperexcitability of peripheral small diameter sensory fibers and painful diabetic neuropathy. Here, we investigated the effect of high-fat diet-induced obesity on the activity of dorsal root ganglion (DRG) sensory neurons and pain perception. We deciphered the underlying cellular mechanisms involving the acid-sensing ion channel 3 (ASIC3). We show that mice made obese through consuming high-fat diet developed the metabolic syndrome and prediabetes that was associated with heat pain hypersensitivity, whereas mechanical sensitivity was not affected. Concurrently, the slow conducting C fibers in the skin of obese mice showed increased activity on heating, whereas their mechanosensitivity was not altered. Although ASIC3 knockout mice fed with high-fat diet became obese, and showed signs of metabolic syndrome and prediabetes, genetic deletion, and in vivo pharmacological inhibition of ASIC3, protected mice from obesity-induced thermal hypersensitivity. We then deciphered the mechanisms involved in the heat hypersensitivity of mice and found that serum from high-fat diet-fed mice was enriched in lysophosphatidylcholine (LPC16:0, LPC18:0, and LPC18:1). These enriched lipid species directly increased the activity of DRG neurons through activating the lipid sensitive ASIC3 channel. Our results identify ASIC3 channel in DRG neurons and circulating lipid species as a mechanism contributing to the hyperexcitability of nociceptive neurons that can cause pain associated with lipid-rich diet consumption and obesity.

Funder

Agence Nationale de la Recherche

Fédération Hospitalo-Universitaire InovPain

Centre National de la Recherche Scientifique

Université Côte d’Azur

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine,Neurology (clinical),Neurology

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