Intermittent fasting-dependent leptin signalling promotes axonal regeneration in the peripheral and central nervous system
File(s)
Author(s)
Chadwick, Jessica
Type
Thesis or dissertation
Abstract
Spinal cord injury affects thousands world- wide and yet clinical therapies remain elusive. This is partially because the central nervous system (CNS) is unable to regenerate. However, the peripheral nervous system (PNS) can mount a regenerative response, facilitating axonal growth and plasticity. Environmental factors such as exercise, diet and sleep have been shown to impact this regenerative capacity. Intermittent fasting (IF) for example, enhances axonal regeneration and functional recovery after sciatic nerve crush (SNC) and spinal cord injury. The endogenous molecular mechanisms for how it does so however, remain outstanding in the field. One of the key regulators of the fasting state within the body is leptin, the satiety hormone responsible for energy homeostasis. Many of leptin’s downstream signalling pathways overlap with established regenerative mechanisms and previous work has characterised leptin’s action in wound healing and regulating injury inflammation. It was hypothesised that leptin may drive the pro-regenerative effects seen with intermittent fasting following injury in the nervous system. RNA sequencing of dorsal root ganglia (DRG) neurons after IF revealed a number of metabolic changes, including significant upregulation of leptin signalling. Validation experiments with qPCR and immunohistochemistry confirmed this, showing neuronal leptin expression increases after SNC injury. To determine if leptin is central to this regenerative phenotype, deletion of the leptin receptor via Cre- injection in leptin receptor (LepR) FLOX mice ablated leptin’s downstream signalling cascades and attenuated the regenerative response seen in IF. Independently of IF, overexpression experiments with AAV-Leptin-GFP viruses followed by either SNC or dorsal column axotomy (DCA) showed leptin enhanced axonal regeneration in both the PNS and CNS, displaying robust regeneration through the lesion site in the spinal cord. Subsequent investigations exploring the molecular mechanisms underlying leptin’s regenerative phenotype found leptin upregulates transcription after spinal cord injury, modulating a dynamic euchromatin environment to facilitate regeneration-associated gene (RAG) expression. In summation, this data outlines a novel therapeutic role of leptin in nerve repair and functional recovery after injury.
Version
Open Access
Date Issued
2022-06-26
Date Awarded
2022-09-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Di Giovanni, Simone
Festenstein, Richard
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)
Rights Embargo Date
2025-08-31