Ketolysis—the catabolism of β-hydroxybutyrate (β-HB) and acetoacetate for fuel—is known to contribute to the development and health of the nervous system. Ketone utilization is highest during neonatal periods, with β-HB uptake and activity of β-HB dehydrogenase 1 (BDH1) decreasing throughout development and into adulthood (Kraus et al., 1974; Bilger and Nehlig, 1992; Nehlig et al., 1991). Acetoacetate prevents hippocampal lesions caused by the inhibition of glycolysis in Wistar rats and increased adenosine triphosphate (ATP) production (Massieu et al., 2003). Likewise, β-HB is neuroprotective and supports synaptic function following glycolytic inhibition in hippocampal slices from rats postnatal day 30 and earlier (Izumi et al., 1998). In disease states, ketogenic diets are neuroprotective in pediatric epilepsy (Sourbron et al., 2020; Henderson et al., 2006), and their use has led to improvements in Alzheimer's disease, cognitive impairment (Taylor et al., 2018), and migraine (Bongiovanni et al., 2021; Di Lorenzo et al., 2019). Together, these findings highlight the importance of metabolic plasticity between glycolysis and ketolysis in the developing and diseased central nervous system.

Little is known about ketone metabolism's contribution to somatosensory nervous system health. Ketone bodies are brought into peripheral tissues by the monocarboxylate transporters (Hugo et al., 2012), after which they are utilized for metabolic and signaling functions (Puchalska and Crawford, 2017; Puchalska and Crawford, 2021). The obligate reaction during ketolysis is the addition of coenzyme A to acetoacetate catalyzed by succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1). Oxct1 mRNA and SCOT protein expression are downregulated in mouse models of neurological diseases, including amyotrophic lateral sclerosis (Szelechowski et al., 2018) and Friedreich's ataxia (Dong et al., 2022). Ketone incorporation in lipid synthesis is disrupted in the sciatic nerve of Trembler mouse models of Charcot-Marie-Tooth (Clouet and Bourre, 1988). We previously published that ketone bodies support neurite outgrowth from dissociated dorsal root ganglia (Cooper et al., 2018b). We also recently showed that ketone bodies are further protective in painful neuropathies by contributing to the detoxification of reactive dicarbonyls, such as methylglyoxal, that are elevated in diabetic neuropathy and directly cause neuronal dysfunction and pain (Enders et al., 2022b). Likewise, our works showed that a ketogenic diet supported the regeneration of lost intraepidermal nerve fibers in a model of peripheral diabetic neuropathy (Enders et al., 2022a) and reversed pain-like behaviors in mouse models of type 1 diabetes (Enders et al., 2022a) and prediabetes (Cooper et al., 2018b). Additionally, sciatic nerve mitochondria from mice fed a ketogenic diet produce less reactive oxygen species (Cooper et al., 2018a). Together, these prior findings suggest ketone metabolism likely plays a vital role in the protective effects of a ketogenic diet in the peripheral nerve.

To understand the contributions of ketone metabolism in the somatosensory nervous system, we used a Cre-lox system to generate a peripheral sensory neuron-specific knockout of Oxct1, referred to as sensory neuron, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice. We tested the hypothesis that ketone body metabolism or signaling was critical for somatosensory nervous system development by exploring potential changes in sensory neuronal phenotypes, peripheral axon integrity, and somatosensation in Adv-KO-SCOT mice. Our results suggest that ketone metabolism in sensory neurons is required for normal epidermal innervation and myelination of large peripheral axons. Sensory behaviors largely remain unchanged in Adv-KO-SCOT mice; however, these animals' response to intraplantar capsaicin was diminished and they demonstrated proprioceptive deficits. These findings provide important insight into processes underlying ketone metabolism in the peripheral nerves. Moreover, these results provide an essential framework for understanding the potential therapeutic effects of a ketogenic diet on somatosensation and pain.