Ketogenic Diet and Exercise Improve Peripheral Neuropathy in a Mouse Model of Metabolic Syndrome.

Metabolic syndrome (MetS) is a growing health concern that increases risk for peripheral neuropathy (PN), defined by nerve degeneration and sensory dysfunction. Although lifestyle strategies, like ketogenic diet (KD) and exercise, are known to mitigate MetS, their efficacy in maintaining nerve health or reversing established PN is less clear. First, in a maintenance paradigm, we tested whether long-term KD could maintain nerve health in mice, as opposed to a Western-style high-fat diet (HFD) that induces MetS PN. Second, in an intervention paradigm of mice with established MetS PN, we compared the efficacy of low-fat standard diet, KD, exercise, and combined KD-exercise interventions in reversing MetS PN. Long-term KD maintained body composition, nerve function, and neuromuscular innervation. In mice with established MetS PN, all interventions improved metabolic parameters and nerve function, albeit to varying extents. Transcriptomic profiling revealed that HFD dysregulated genes related to cytoskeletal dynamics and inflammation in sciatic nerve, with interventions partially reversing these changes. In muscle, dietary interventions modulated fatty acid and amino acid metabolism. Notably, exercise generated a unique gene expression signature in nerve and muscle. These findings support KD and exercise as promising approaches for treating MetS PN and offer mechanistic insights into their therapeutic benefits. ARTICLE HIGHLIGHTS: Metabolic syndrome (MetS) increases risk for peripheral neuropathy (PN), a progressive nerve disorder with limited treatment options. We examined whether long-term ketogenic diet (KD) could maintain nerve health, and whether KD, exercise, or both could reverse established MetS PN. Maintenance KD preserved body composition, liver health, and nerve function, while all interventions improved metabolic and nerve outcomes to varying degrees. Transcriptomic profiling of sciatic nerve and gastrocnemius muscle revealed partial reversal of MetS-induced inflammatory, cytoskeletal, and metabolic gene alterations. These findings highlight KD and exercise for treating MetS PN.