Feeding and moving the nerve: a metabolic cure for neuropathy?
Aims: To investigate whether a long-term ketogenic diet (KD) can maintain peripheral nerve health and whether KD, exercise, or their combination can reverse established peripheral neuropathy (PN) in a mouse model of metabolic syndrome (MetS).
Methods: Male C57BL/6J mice were studied in two paradigms: (1) a maintenance model comparing long-term KD (90% kcal fat) with high-fat diet (HFD) and standard diet; and (2) an intervention model in HFD-induced MetS PN, randomised to standard diet, KD, exercise, or combined KD-exercise. Outcomes included metabolic phenotyping, nerve conduction velocities (NCVs), intraepidermal nerve fibre density (IENFD), neuromuscular junction (NMJ) integrity, and transcriptomic profiling of sciatic nerve and muscle.
Results: Long-term KD preserved body composition, liver health, and peripheral nerve structure and function, whereas HFD induced metabolic dysfunction and PN. In mice with established PN, all interventions improved metabolic parameters and large-fibre nerve function. However, only standard diet restored small fibre density, while exercise improved NMJ innervation. Combined KD-exercise had the greatest effect on body composition. Transcriptomic analyses demonstrated that HFD upregulated inflammatory, cytoskeletal, and extracellular matrix pathways, which were partially reversed by dietary and exercise interventions. Exercise induced a distinct gene expression signature, particularly in pathways related to calcium and insulin signalling.
Conclusions: KD maintains peripheral nerve health and, together with exercise, improves neuropathy in MetS. These benefits are mediated through metabolic reprogramming and modulation of inflammatory and structural pathways, supporting lifestyle interventions as potential disease-modifying strategies for MetS-associated PN.
Comments: This is a comprehensive and mechanistically rich preclinical study addressing an important and clinically relevant question - whether lifestyle interventions can meaningfully modify the trajectory of metabolic neuropathy. The dual design, examining both prevention and reversal paradigms, strengthens the overall message and allows a more nuanced interpretation of how KD and exercise influence nerve health at different disease stages. The use of transcriptomics provides valuable insight into the molecular pathways underpinning these effects within the nerve itself.
The demonstration that KD preserves nerve function longitudinally, and that exercise exerts distinct molecular effects, is particularly novel and relevant to translational strategies. While KD appears to improve large fibre measures in established disease, it does not restore small fibre density, in contrast to the standard diet intervention. This divergence highlights the complexity of neuropathy pathophysiology and suggests that metabolic improvements alone may not uniformly translate across fibre subtypes. The distinct molecular signature associated with exercise is also noteworthy and reinforces its independent role beyond weight or glycaemic effects.
The study was limited to male mice; given known sex differences in metabolic regulation, future research should include female models to ensure clinical generalisability. The exploratory transcriptomic analyses provide a useful foundation for further mechanistic validation.
Overall, this study provides compelling mechanistic evidence for lifestyle interventions in MetS-associated neuropathy and offers a strong basis for future translational and clinical studies.
Shazli Azmi
Reference. Eid SA, Jaisil P, Guo K, Hayes JM, Pacut C, Rigan DM, Carter A, Teener SJ, Kim B, Kiriluk C, Lentz W, Miller CM, Webber-Davis I, McQuown H, Jang DG, Patterson A, Koubek EJ, Bridges D, Hur J, Meyer JD, Feldman EL. Ketogenic Diet and Exercise Improve Peripheral Neuropathy in a Mouse Model of Metabolic Syndrome. Diabetes. 2026 Mar 20:db251015. doi: 10.2337/db25-1015. Epub ahead of print. PMID: 41861283.
