Medium Chain Triglycerides and Ketogenesis

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Background: Medium fatty acids chain occur naturally as medium chain triglycerides (MCT) and can be found in coconut and palm oils. MCT have different forms and can be purchased over the counter as a dietary supplement (MCT oil). Unlike other fatty acid, MCT provide immediate energy because they are able to cross the double mitochondrial membrane very rapidly, and this results in the production of ketone bodies (KB). Of interest, many studies have shown that MCT supplements rise circulating KB and enhance athletic performance. However, the biological actions of MCT, and the mechanisms by which MCT may enhance ketone body production (Ketogenesis) have been relatively understudied. Hence, the major aims of this proposal are to elucidate the mechanisms by which MCT supplement increases ketogenesis in liver, and subsequently this will enhance liver mitochondrial function. Hypothesis: We hypothesize that MCT supplement increases circulation KB by augmenting the fate committing ketogenic enzyme mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2), as a result this will improve hepatic mitochondrial function. Methodology: We will utilize a number of cell culture and animal approaches to reveal how MCT supplement augment KB production rates in the liver. This includes culturing and treating liver cell line (HepG2) with different forms and concentrations of MCT, and assessing the ketogenesis enzymes and hepatic mitochondrial function. Furthermore, we will subject mice to MCT-rich diet for 12 weeks to determine whether MCT treatment increases circulating KB, enhances ketogenic pathway (e.g. HMGCS2) and hepatic mitochondrial function via mRNA/protein expression profiling of liver extracts. Moreover, energy expenditure and energy substrate preference will be determined in mice subjected to MCT-rich diet via indirect calorimetry measurements. Aims: This research proposal will encompass 2 specific aims; (1) To determine whether the ketogenic enzyme (HMGCS2) is augmented in the liver following treatment with MCT, and (2) to assess whether MCT treatment increases hepatic mitochondrial function. In aim 1, we will treat cultured HepG2 with different forms and concentrations of MCT, and assess mRNA/protein expression profile of ketogenic metabolic pathway. Furthermore, we will measure circulating KB in mice subjected to MCT-rich diet and assess their whole body O2 consumption rates and respiratory exchange ratio via indirect calorimetry. In aim 2, we will assess a number of key factors involved in mitochondrial function. Impact: Our findings will yield insight into the mechanism by which MCT supplement enhances ketone body production rates and hepatic mitochondrial function. Moreover, the results of this research program also provide significant insights into what "claims" should be allowed for manufacturers who market MCT as an over-the-counter nutraceutical dietary supplement to augment KB.