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. 2010 Aug 20;285(34):25950-6.
doi: 10.1074/jbc.M110.138198. Epub 2010 Jun 7.

A Ketone Ester Diet Increases Brain malonyl-CoA and Uncoupling Proteins 4 and 5 While Decreasing Food Intake in the Normal Wistar Rat

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Free PMC article

A Ketone Ester Diet Increases Brain malonyl-CoA and Uncoupling Proteins 4 and 5 While Decreasing Food Intake in the Normal Wistar Rat

Yoshihiro Kashiwaya et al. J Biol Chem. .
Free PMC article

Abstract

Three groups of male Wistar rats were pair fed NIH-31 diets for 14 days to which were added 30% of calories as corn starch, palm oil, or R-3-hydroxybutyrate-R-1,3-butanediol monoester (3HB-BD ester). On the 14th day, animal brains were removed by freeze-blowing, and brain metabolites measured. Animals fed the ketone ester diet had elevated mean blood ketone bodies of 3.5 mm and lowered plasma glucose, insulin, and leptin. Despite the decreased plasma leptin, feeding the ketone ester diet ad lib decreased voluntary food intake 2-fold for 6 days while brain malonyl-CoA was increased by about 25% in ketone-fed group but not in the palm oil fed group. Unlike the acute effects of ketone body metabolism in the perfused working heart, there was no increased reduction in brain free mitochondrial [NAD(+)]/[NADH] ratio nor in the free energy of ATP hydrolysis, which was compatible with the observed 1.5-fold increase in brain uncoupling proteins 4 and 5. Feeding ketone ester or palm oil supplemented diets decreased brain L-glutamate by 15-20% and GABA by about 34% supporting the view that fatty acids as well as ketone bodies can be metabolized by the brain.

Figures

FIGURE 1.
FIGURE 1.
CE-MS analysis of rat whole brain extracts for acyl-CoA compounds. Selected ion chromatographic tracings for the molecular anion mass values (M-1) for: (1) [13C4]succinyl-CoA (m/z: 872), (2) succinyl-CoA (m/z: 868), (3) CoA (m/z:766), (4) acetyl-CoA (m/z:808), (5) malonyl- CoA (m/z: 852), (6) [13C2]acetyl-CoA (m/z: 810) and (7) [13C3]malonyl-CoA (m/z: 855) from rat brain tissues extracted with chloroform and analyzed by capillary electrophoresis mass spectrometry according to previously described methods.
FIGURE 2.
FIGURE 2.
Food intake of 3 diets in ad lib fed rats. Food intake of starch-, fat-, and ketone-supplemented diet animal groups. All animals were fed ad lib for 3 h every day, and their food intake was measured for 6 days. Data are presented as means ± S.E. (n = 6).
FIGURE 3.
FIGURE 3.
Uncoupling proteins 4 and 5 in rat brain fed starch-, palm oil-, or ketone ester-supplemented diets. Levels of mitochondrial UCP4 (panel A) and UCP5 (panel B) in the brains of rats (n = 6 for fat and ketones, n = 7 for starch) fed a diet supplemented with palm oil (fat), starch, or ketone ester. **, p < 0.01; ***, p < 0.001 compared with fat-supplemented diet, ††, p < 0.01; †††, p < 0.001 compared with starch-supplemented diet.

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