Reduced mitochondrial reactive oxygen species production in peripheral nerves of mice fed a ketogenic diet.

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FINDINGS: What is the central question of this study? Do peripheral sensory neurons metabolize fat-based fuel sources, and does a ketogenic diet modify these processes? What is the main finding and its importance We show that peripheral axons from mice fed a ketogenic diet respond to fat-based fuel sources with reduced respiration and H2 O2 emission compared with mice fed a control diet. These results add to our understanding of the responses of sensory neurons to neuropathy associated with poor diet, obesity and metabolic syndrome. These findings should be incorporated into current ideas of axonal protection and might identify how dietary interventions may change mitochondrial function in settings of sensory dysfunction. ABSTRACT: Metabolic syndrome and obesity are increasing epidemics that significantly impact the peripheral nervous system and lead to negative changes in sensation and peripheral nerve function. Research to understand the consequences of diet, obesity and fuel usage in sensory neurons has commonly focused on glucose metabolism. Here, we tested whether mouse sensory neurons and nerves have the capacity to metabolize fat-based fuels (palmitoyl-CoA) and whether these effects are altered by feeding of a ketogenic (90% kcal fat) diet compared with a control diet (14% kcal fat). Male C57Bl/6 mice were placed on the diets for 10 weeks, and after the mice were killed, the dorsal root ganglion (DRG) and sciatic nerve (SN) were placed in an Oroboros oxygraph-2K to examine diet-induced alterations in metabolism (respiration) of palmitoyl-CoA and H2 O2 emission (fluorescence). In addition, RNAseq was performed on the DRG of mice fed a control or a ketogenic diet for 12 weeks, and genes associated with mitochondrial respiratory function were analysed. Our results suggest that the sciatic nerves from mice fed a ketogenic diet display reduced O2 respiration and H2 O2 emission when metabolizing palmitoyl-CoA compared with mice fed a control diet. Assessments of changes in mRNA gene expression reveal alterations in genes encoding the NADH dehydrogenase complex and complex IV, which could alter production of reactive oxygen species. These new findings highlight the ability of sensory neurons and axons to oxidize fat-based fuel sources and show that these mechanisms are adaptable to dietary changes.