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Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIIT-CR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerves, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMPK. We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerves. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression. Article Highlights: Diet and exercise are recommended for treating peripheral neuropathy in prediabetes. To identify the optimal regimen and the underlying neuroprotective mechanisms, we compared the effects of caloric restriction (CR), high-intensity interval training (HIIT), and their combination (HIIT-CR), on metabolic and neuropathy outcomes following high-fat diet feeding. While all interventions improved neuropathy, CR and HIIT-CR, but not HIIT alone, improved metabolic profiles and promoted insulin sensitivity in peripheral nerves of high-fat diet–fed mice. In vitro, palmitate-treated Schwann cells developed insulin resistance, which was reversed by AMPK activation. CR, alone or combined with HIIT, ameliorates neuropathy by restoring nerve insulin sensitivity. [ABSTRACT FROM AUTHOR]