Dietary-dependent sensitization of neuronal leptin signaling promotes neural repair after injury via cAMP and gene transcription.

Dietary-dependent shifts, ranging from metabolic dysfunction to health, involve transitions in key signaling pathways. Dietary regimens can influence nervous system repair, but whether conserved, diet-specific mechanisms can enhance neuronal regeneration by directly sensitizing neuronal signaling remains unclear. We found that in mice, in contrast to a neuropathy-inducing high-fat diet that causes leptin resistance, intermittent fasting (IF) enhances leptin sensitivity in dorsal root ganglia sensory neurons. Deletion of leptin receptors in sensory neurons impairs IF-induced regeneration. Systemic leptin or leptin neuronal overexpression promote axonal repair after sciatic nerve crush and spinal cord injury via endocrine or autocrine mechanism, respectively. Leptin-dependent axon growth requires cyclic AMP (cAMP) signaling, transcriptional activity, and regenerative gene expression to support axon growth after injury. Unexpectedly, leptin, whose canonical function is to control feeding, promotes neuronal regenerative signaling, highlighting a novel role in nervous system regeneration and providing insights into diet-dependent neurorepair mechanisms.