Ketolysis is required for the proper development and function of the somatosensory nervous system

Enders, Jonathan; Jack, Jarrid; Thomas, Sarah; Lynch, Paige; Lasnier, Sarah; Cao, Xin; Swanson, M. Taylor; Ryals, Janelle M.; Thyfault, John P.; Puchalska, Patrycja; Crawford, Peter A.; Wright, Douglas E.

doi:10.1016/j.expneurol.2023.114428

Cited by 4 publications

(2 citation statements)

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Section: Discussionmentioning

confidence: 99%

“…Macrophages do not oxidize BHB 52 . However, neurons 53,54 , CD4 + T cells 34,35 , CD8 + T cells 34,36 , and microglia 41 do, results in the formation of ATP and intermediate metabolites, such as acetyl-CoA and succinate. Although S-BHB is oxidized much more slowly than R-BHB 2 , both forms of BHB acid reduced inflammation to a similar degree (Figure 3B), suggesting both R-and S-BHB appear to function as signaling molecules rather than energy metabolites for achieving anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

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A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

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Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB’s anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

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Metabolic Messengers: ketone bodies

Nelson,

Queathem,

Puchalska

et al. 2023

Nat Metab

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ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice

Enders

Thomas

Lynch

et al. 2023

Preprint

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Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.

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Ketolysis is required for the proper development and function of the somatosensory nervous system

Cited by 4 publications

References 50 publications

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Metabolic Messengers: ketone bodies

ATP-Gated Potassium Channels Contribute to Ketogenic Diet-Mediated Analgesia in Mice

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