Abstract
The ketogenic diet (KD) has been utilized as a dietary therapeutic for nearly a century. One experimental model particularly responsive to the KD is the BTBRT+tf/j (BTBR) mouse, which displays phenotypic characteristics of autism spectrum disorder (ASD) and insulin resistance. Recently, the study of impaired mitochondrial function has become a focal point of research investigating the pathophysiology of ASD. As highly dynamic organelles, mitochondria undergo constant fluctuations in morphology, biogenesis, and quality control in order to maintain cellular homeostasis. An important modifier of mitochondrial dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondrial dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57Bl/6 (B6) and BTBR mice were age-matched to 5 weeks of age before being fed standard chow (CD, 13% kcal fat) or a KD (75% kcal fat) for 10–14 days. Analysis of brain tissue identified differences in mitochondrial gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondrial proteins in the liver, despite increased gene expression. Consistent with decreased mitochondrial proteins, we also observed decreased mtDNA for all mice on the KD, demonstrating that the KD reduces the total amount of mitochondria in the liver. In order to explain the discrepancy between protein levels and gene expression, we investigated whether mitochondrial turnover via mitophagy was increased. To this end, we examined expression levels of the mitophagy regulator BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3). BNIP3 gene and protein expression were significantly elevated in liver of KD animals (p < 0.05), indicating the potential activation of mitophagy. Therefore, consumption of a KD exerts highly tissue-specific effects, ultimately increasing mitochondrial turnover in the liver, while gene and protein expression in the brain remaining tightly regulated.
Highlights
The ketogenic diet (KD) has been utilized as a dietary therapy in clinical settings since the early 1920’s and is well-documented in mitigating symptoms for a number of diseases, including epilepsy (Rho, 2015), autism spectrum disorder (ASD; Ruskin et al, 2013), and diabetes (Feinman et al, 2014)
The mechanism(s) of action through which the KD imparts its beneficial effects are yet to be elucidated, we sought to examine the impact of the KD on mitochondrial dynamics in B6 and BTBR mice, a model known to be highly responsive to the KD (Ruskin et al, 2013)
We examined mitochondrial function and aspects of mitochondrial dynamics in the liver and brain of B6 and BTBR mice fed either a CD or KD
Summary
The ketogenic diet (KD) has been utilized as a dietary therapy in clinical settings since the early 1920’s and is well-documented in mitigating symptoms for a number of diseases, including epilepsy (Rho, 2015), autism spectrum disorder (ASD; Ruskin et al, 2013), and diabetes (Feinman et al, 2014). The by-product of this metabolic shift, are synthesized in the liver and consumed by major organ systems such as the brain, heart, and skeletal muscle as a major fuel source (Kossoff et al, 2009). The mechanisms of ketone body generation and utilization are wellunderstood, the tissue-specific impact of KD metabolism has yet to be examined. As the principal site of fatty acid metabolism through β-oxidation, assessment of mitochondrial function through oxidative phosphorylation (OXPHOS) efficiency is a primary measure in KD interventions (Gano et al, 2014; Vidali et al, 2015). The literature primarily focuses on the relationship between the KD and brain tissue (Veech, 2004; Masino and Rho, 2012; Milder and Patel, 2012), failing to examine the tissue responsible for ketogenesis—the liver
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