OBESITY-INDUCED ENDOTHELIAL FENESTRATION AND CAPILLARY LEAKAGE CONTRIBUTE TO INCREASED PAIN SENSATION.

Peripheral pain sensation is regulated by interactions between sensory nerves and various tissue cells. In obese patients with painful small fiber neuropathy, skin sensory nerves are often hypersensitive. While obesity is known to cause circulation-related vascular abnormalities, how these changes affect sensory dysfunction is not fully understood. In this study, we found that in a diet-induced obesity mouse model, skin capillaries become fenestrated, allowing insulin to diffuse into the avascular epidermis. This exposure triggers the production and secretion of nerve growth factor (NGF) from epidermal keratinocytes via insulin signaling with the forkhead box O1 (FOXO1) transcription factor. Elevated NGF leads to heightened sensory hypersensitivity by enhancing transient receptor potential vanilloid subtype 1 (TRPV1) in sensory nerves. Controlling capillary permeability reduces abnormal NGF expression and attenuates pain hypersensitivity. These findings nominate peripheral nerve-associated capillary permeability as a novel therapeutic target in obesity-associated sensory dysfunction.