Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: Estimated potential contribution to brain energy metabolism

Abstract

Objective

In humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2) ¹³C-β-hydroxybutyrate and ¹³C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism.

Methods

Eight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation. Using isotope ratio mass spectroscopy, ¹³C-D-β-hydroxybutyrate and ¹³C-trioctanoate β-oxidation to ¹³CO₂ was measured over 12 h on the pre- and post-MCT metabolic study days.

Results

On the post-MCT metabolic study day, plasma ketones (β-hydroxybutyrate plus acetoacetate) peaked at 476 μM, with a mean value throughout the study day of 290 μM. Post-MCT, ¹³C-trioctanoate β-oxidation was significantly lower 1 to 8 h later but higher 10 to 12 h later. MCT supplementation did not significantly alter ¹³C-D-β-hydroxybutyrate oxidation.

Conclusions

This MCT supplementation protocol was mildly and safely ketogenic and had no side effects in healthy humans on their regular diet. This degree of ketonemia is estimated to contribute up to 8% to 9% of brain energy metabolism.

Introduction

The human brain has an energy requirement disproportionate to its size; although it represents only ∼2% of adult weight, it uses ∼22% of the body’s oxygen consumption, mostly for aerobic glucose oxidation [1]. In an ad libitum–fed, healthy adult, roughly 97% of the brain’s requirement is met directly or indirectly by glucose, with the remaining 3% coming primarily from ketones (β-hydroxybutyrate [β-OHB], acetoacetate [AcAc], and acetone) [1], [2]. Under ketogenic conditions, β-oxidation of fatty acids in the liver [3] and possibly in astrocytes [4] produces most, if not all, the ketones used by the brain. Under normal conditions, plasma ketone concentrations are relatively low (≤0.2 mM), but during ketogenic conditions, i.e., extended fasting or a very high-fat ketogenic diet, plasma ketones can increase to 5 mM, at which point they provide up to two-thirds of the brain’s energy requirement [5]. Monocarboxylate transporter-1 in the blood–brain barrier is responsible for ketone transfer to the brain [6].

Medium-chain triacylglycerol (MCT) oils are composed of fatty acids of 8 to 12 carbons, mostly octanoate (8:0) and decanoate (10:0). MCTs are mainly absorbed as free fatty acids directly from the portal vein, thus reaching the liver faster than long-chain fatty acids (≥14 carbons), which are absorbed from the small intestine and lymphatic system. In the liver, MCT β-oxidation is rapid because it does not need to be activated by coenzyme A, making MCT a good ketogenic substrate [7]. Several studies have described the short-term efficacy of MCTs for ketogenesis and for supporting normal cognitive function in the elderly and during experimentally induced hypoglycemia [8], [9], [10], [11], [12]. Long-term supplementation with MCTs may potentiate the ketogenic response to a single dose of MCT [13].

In the elderly, 10% to 15% lower brain glucose uptake has been widely reported, a value that increases to 20% to 25% in Alzheimer’s disease [14], [15], [16], [17]. Several studies have suggested that the uptake and/or use of glucose by the brain can deteriorate long before the normal threshold of the clinical symptoms of cognitive decline, i.e., in young adult carriers of apolipoprotein E4, an important genetic risk factor for Alzheimer’s disease, and in those with a maternal history of Alzheimer’s disease [17]. In the absence of any effective strategy to prevent or reverse the aging-related decline in brain glucose uptake, mildly stimulating ketogenesis may be a way to bypass the significant deficit in brain glucose uptake in persons with or at risk of developing aging-related cognitive decline [17], [18], [19]. The high-fat ketogenic diet has shown efficacy in the treatment of epilepsy [20], [21]. In addition to trials of ketogenic supplements in Alzheimer’s disease [9], [13], this approach is being assessed for the treatment of other neurologic disorders, including Parkinson’s disease, brain tumors, and stroke [18], [22], [23].

The three aims of the present study were to 1) determine whether 4 wk of supplementation with MCTs could induce a relatively sustained yet safe level of ketonemia in healthy adults consuming their usual diets, 2) evaluate labeled ketone and octanoate oxidation before and after MCT supplementation, and 3) estimate a plasma ketone level theoretically capable of replacing the apparent brain fuel deficit caused by lower brain glucose uptake in Alzheimer’s disease.