Painful diabetic neuropathy (DN) affecting small sensory neurons is one of the most common complications of obesity and type 2 diabetes. While emerging clinical evidence demonstrates that DN is associated with dyslipidemia, the complex molecular and cellular neurobiology triggering the disease is unknown. Emerging evidence demonstrates the important contribution of complex pathways including endoplasmic reticulum stress and inflammation. Recent OMICs data analyzing peripheral nervous tissue (Dorsal root ganglia (DRG) and associated nerves) of obese individuals have also highlighted alterations in lipid nuclear receptors, which provide novel insight into the onset of DN. Liver X Receptors (LXR) α and β are nuclear transcription factors that respond to cholesterol or fatty acid metabolites. Nuclear LXRs control gene programs in liver cells, adipocytes, and macrophages to regulate lipid metabolism, inflammation and ER stress though the specific physiological role of LXRs in neurons is difficult to interpret given its broad tissue expression. Our tissue specific deletion model unmasks an important role of LXR in small sensory neurons in type 2 DN pathogenesis. Our results show that LXR deletion in sensory neurons worsens the hypersensitivity induced by a High fat Diet (HFD) associated with changes in DRG gene. In addition, treatment with the LXR agonist GW4965 improves the HFD-induced mechanical allodynia in vivo and protects mice DRG sensory neurons from lipid-induced ER stress in vitro and in vivo (ribo-tag model), further confirming a protective role for LXR in DN. Our data suggest that the lipid sensor LXRs in small sensory neurons could respond to dietary lipid to potentially maintain normal PNS function in the face of high-fat nutrition.
V. Aubert: None.