TRANSCRIPTIONAL REGULATION OF NERVE GROWTH FACTOR IN EPIDERMAL KERATINOCYTES THROUGH THE INSULIN SIGNALING PATHWAY IN THE DIET-INDUCED OBESITY MOUSE MODEL.

Abstract

Obesity or pre-diabetic patients with painful small fiber neuropathy develop sensory hypersensitivity, sensory axon degeneration, and damaged microvasculature, all lacking current effective therapeutics. We have recently found that keratinocytes-derived nerve growth factor (NGF) sensitizes skin nociceptive pain in a diet-induced obesity mouse model (Koui et al. 2025). To address the regulatory mechanism governing NGF expression in response to elevated glucose and insulin levels, a common feature of obesity and pre-diabetes, I cultured mouse and human keratinocytes with glucose and insulin treatments. I observed that the upregulation of NGF expression in response to high levels of insulin occurs in both mouse and human keratinocytes. Forkhead domain class O transcription factors (FOXOs) were shown to control longevity by sensing environmental cues such as hormones, nutrient, oxidative stress and energy metabolism via signaling through the insulin, AKT/mTOR, JNK and AMPK pathways. My data have illustrated the expression of FOXO1 and FOXK1 in cultured human keratinocytes, accompanied by translocation of FOXO1 from the nucleus to the cytoplasm upon insulin stimulation. Knockdown experiments indicate that FOXO1 acts as a suppressor, whereas FOXK1 serves as an activator, in regulating NGF expression in response to insulin signaling. Given that keratinocytes-derived NGF sensitizes sensory nerves in obese skin and induces nociceptive pain, these findings suggest that NGF and its regulatory components, including insulin signaling, could be potential therapeutic targets for managing neuropathic pain in obesity patients.