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

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.The metabolism of ketone bodies in the working perfused heart increased the supply of mitochondrial NADH and the ⌬G of ATP hydrolysis (1). Other than the observation that ketone bodies can replace glucose as the major energy substrate in brain (2), little is known about the precise effects of ketone metabolism in brain in vivo. The elevation of ketone bodies (3-hydroxybutyrate and acetoacetate) and free fatty acids through ketogenic diets have been used for almost a century to treat drug refractory epilepsy (3, 4). In addition, it has been suggested that mild ketosis might be an effective treatment for a number of neurodegenerative and other diseases (5-7). We therefore undertook a broad survey of the effects of a ketone ester-and a fat-supplemented diet on several of the pathways of intermediary and energy metabolism in rat brain.Prevention of postmortal changes, necessary for the accurate determination of in vivo redox and phosphorylation states in brain, require rapid inactivation of tissue, which was accomplished by freeze-blowing (8, 9 Elevation of blood ketone bodies, by either fasting or high fat diets, results in elevation of both blood ketone bodies and free fatty acids. Therefore, prior to this report, it has not been possible to investigate ketone body metabolism in brain independent of the effects induced by elevation of plasma free fatty acids.More recently, ketogenic diets have been used in the treatment of obesity where it has been shown that high protein, low carbohydrate diets decreased appetite, sensation of hunger, and food intake in hospitalized patients(10). The intraventricular infusion of 3-hydroxybutyrate (11, 12) or intravenous administration of its precursor 1,3-butanediol (13), have previously been shown to decrease food intake in the rat as has intraperitoneal injections of 3-hydroxybutyrate or 1,3-butanediol in the pigmy goat (14). Subcutaneo...

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

“…Feeding the KME diet resulted in a signifi cant decrease in both L -glutamate and GABA. This observation provides additional support for the notion that the antiepileptic effect of KDs may result from the reduction in the excitatory amino acid glutamate associated with their use ( 77 ).…”

“…Two KEs are known to be under current study: a ) 1,3-butanediol monoester of ␤ HB (KME) ( 77,(79)(80)(81)(82)(83)(84) and b ) 3GHB ( 48,85,86 ). Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of ␤ HB are safe and well tolerated in animals ( 80,86 ), and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans ( 79 ).…”

Ketone ester effects on metabolism and transcription

“…A RAT LOWERS THE BLOOD GLUCOSE, WHILE AT THE SAME TIME LOWERING BLOOD INSULIN, DEMONSTRATING THAT KETOSIS INCREASES INSULIN SENSITIVITY Blood glucose decreased by about 50% from 5 to 2.8 mM while insulin decreased from 0.54 to 0.26 ng/ml in rats fed a diet where 30% of the calories from starch were replaced with ketone esters ( 20 ). Plasma leptin was also decreased from 3.12 to 1.83 ng/ml in rats, where ketone esters were substituted equi-calorically for starch.…”

Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion

“…Thus, acute infusion of 3HB into Langendorff-perfused rat hearts leads to a 25% increase in hydraulic work effi ciency of the heart ( 50 ) (36% when combined with insulin). Furthermore, very recent work shows that feeding mice a ketone ester diet affects both brown fat ( 51 ) and brain metabolism ( 52 ). Thus, the effects of Intralipid infusion that were previously ascribed to acute increases in lipids may in fact be due to increased ketone concentration.…”