Abstract
Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.
Highlights
Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 signaling pathway, potentially leading to a range of positive medical and health-related effects
As wideranging therapeutic benefits of the classical ketogenic diet have been associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling [1, 4, 8, 9] (Fig. 1A), we employed Dictyostelium to investigate the effects of the medium-chain triglyceride (MCT) diet constituents decanoic acid and octanoic acid on this activity
We initially assessed the effects of these medium-chain fatty acids on Dictyostelium unicellular growth and multicellular development to establish relevant concentrations of decanoic acid and octanoic acid to investigate in this model
Summary
Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Eleanor C. Inhibition of mechanistic target of rapamycin complex 1 (mTORC1) has been suggested as a common mechanism contributing to the therapeutic benefits of ketogenic diets through a reduction in glucose and insulin [1,2,3,4] This inhibitory activity may provide a component of the therapeutic efficacy of these diets in the treatment of patients with drug-resistant epilepsies [5], cancers [6], and neurodegenerative disorders [7], and in providing lifespan extension [4]. We initially show that decanoic acid causes a reduction of mTORC1 activity in a structurally specific manner in Dictyostelium, in the absence of insulin and in the presence of glucose, suggesting a specific molecular mechanism for decanoic acid in regulating this pathway To identify this mechanism, we screened a mutant library to identify a decanoic acid-resistant mutant lacking a UBX domain-containing protein (UBXD18) that is partially resistant to the effects of decanoic acid on growth and mTORC1 signaling. We translate our findings to a rat hippocampal slice model and astrocytes derived from patients with the neurodevelopmental disorder TSC, to demonstrate that decanoic acid reduces normal and dysregulated mTORC1 signaling in mammalian systems
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