Perturbation of human cerebral energetics with chronic ketosis

It is well known that the human brain switches from its primary fuel of glucose to (largely) ketones under conditions such as fasting, certain diets and severe exercise. Whether this switch is accompanied by cerebral metabolic and energetic shifts is unknown. This question is relevant, particularly given the increasing frequency with which such diets are encountered in the population, as well as the fact that ketotic diets have been shown to affect brain function in several disorders, e.g., the success of the ketogenic diet to treat epilepsy and improve Parkinsons' symptomatology and the Atkins' diet in also improving seizure control in epilepsy 1, 2 – 3. We used high field 31P whole brain spectroscopic imaging to study healthy moderately obese human (n=5, mean age 36.010.4 years) subjects, examining them prior to initiating a very low carbohydrate diet and after 4 weeks of sustaining this diet. For optimum diet control, meals from a licensed caterer were provided to the subjects, and the macronutrient distribution of the diet was 65% fat: 30% protein: 5% carbohydrate. The mean body mass index at baseline was 34.23.1, and after 4 weeks of the diet was 30.72.4. Weight loss was achieved by all volunteers, averaging 8.41.8 kg. 31P spectroscopic imaging was performed at 4Tesla (Varian Inova, whole body MR system) using a pulse acquire acquisition utilizing a three-dimensional spherical sampling scheme (131313, FOV = 242424 cm, ref. 4). Including scout imaging and calibrations, the duration of the 31P study was 75 min. The 31P acquisition has an effective sampling radius of 1.4 cm; previous studies have shown the reproducibility of the 31P acquisition is 10%. Analysis was performed using single voxel reconstructions, with curve fitting for 9 resonances including PCr, -ATP, Pi, phosphomonoesters, phosphodiesters. Quantification was performed accounting for tissue volume, coil loading and relaxation. A moderate ketosis was achieved in all subjects, with plasma BHB rising from 0.240.05 to 1.640.93. Spectra from subject 3 (hypothalamus) is shown in the figure 1, showing PCr, ATP and inorganic phosphate Pi. Data and loci of spectral analysis are shown in the Table 1. The ATP concentrations in the thalamus, hypothalamus and hippocampus rose significantly between D0 to D28. The hypothalamus increased from 2.680.24 mM to 3.180.33 mM ATP. Cerebral energetics changed with use of a ketotic diet, with increased ATP concentrations in the hypothalamus, thalamus and hippocampus. In this limited group no significant changes were detected in PCr concentrations. The largest change was seen in the hypothalamus, and is consistent with a view that lower structures demonstrate greater energetic sensitivity to fuel selection.