Novel ketone diet enhances physical and cognitive performance.

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson's disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.A.J.M. thanks the Research Councils UK for supporting his Academic Fellowship. This work was supported by the Defense Advanced Research Projects Agency.This is the final version of the article. It first appeared from FASEB at https://doi.org/10.1096/fj.201600773R

Elongase Reactions as Control Points in Long-Chain Polyunsaturated Fatty Acid Synthesis

Extent: 9p.Background: Δ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA. Methodology/Principal Findings: The substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C20 and C22 polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3. Conclusions: The competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.Melissa K. Gregory, Robert A. Gibson, Rebecca J. Cook-Johnson, Leslie G. Cleland and Michael J. Jame

n-6 fatty acid metabolism in the newborn infant: is linoleic acid sufficient to meet the demand for arachidonic acid?

Two compartmental models were developed to assess the contributions of linoleic acid, 18:2n-6, and di-homo-g-linoelic acid, 20:3n-6, toward maintaining plasma homeostasis concentrations of arachidonic acid, 20:4n-6, in newborn infants. Ten infants received oral doses of 13C-U-18:2n-6 and 2H5-20:3n-6 ethyl esters (100 and 2 mg kg−1, respectively). Rate constant coefficients of n-6 FAs were determined from the time-course concentrations of labeled-FAs and endogenous plasma n-6 FA values were used to approximate steady state concentrations. Eight percent (range: 2-21%) of plasma 13C-U-18:2n-6 was utilized for synthesis of 13C -18:3n-6, -20:2n-6 and -20:3n-6 and 70% of 13C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13C-20:4n-6. The percentage of 2H5- 20:3n-6 converted to 2H5-20:4n-6 was only 26%. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g kg−1 d−1 (CV: 0.58) and 4.3 mg kg−1 d−1 (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g kg−1 d−1 (± 1.7) and 2.8 mg kg−1 d−1 (± 2.2), respectively. Infants required additional 18:2n-6 (1.2 g kg−1 d−1) above predicted intake amounts to maintain plasma concentrations of 18:2n-6. The percent conversion of 18:2n-6 to 20:4n-6 was incapable of sustaining plasma 20:4n-6 concentrations in nearly all subjects necessitating a supplemental intake of ~ 4 mg kg−1 d−1 of 20:4n-6

n-6 fatty acid metabolism in the newborn infant: is linoleic acid sufficient to meet the demand for arachidonic acid?

Two compartmental models were developed to assess the contributions of linoleic acid, 18:2n-6, and di-homo-g-linoelic acid, 20:3n-6, toward maintaining plasma homeostasis concentrations of arachidonic acid, 20:4n-6, in newborn infants. Ten infants received oral doses of 13C-U-18:2n-6 and 2H5-20:3n-6 ethyl esters (100 and 2 mg kg−1, respectively). Rate constant coefficients of n-6 FAs were determined from the time-course concentrations of labeled-FAs and endogenous plasma n-6 FA values were used to approximate steady state concentrations. Eight percent (range: 2-21%) of plasma 13C-U-18:2n-6 was utilized for synthesis of 13C -18:3n-6, -20:2n-6 and -20:3n-6 and 70% of 13C-20:3n-6 (mean, CV: 0.26) was available for synthesis of 13C-20:4n-6. The percentage of 2H5- 20:3n-6 converted to 2H5-20:4n-6 was only 26%. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g kg−1 d−1 (CV: 0.58) and 4.3 mg kg−1 d−1 (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g kg−1 d−1 (± 1.7) and 2.8 mg kg−1 d−1 (± 2.2), respectively. Infants required additional 18:2n-6 (1.2 g kg−1 d−1) above predicted intake amounts to maintain plasma concentrations of 18:2n-6. The percent conversion of 18:2n-6 to 20:4n-6 was incapable of sustaining plasma 20:4n-6 concentrations in nearly all subjects necessitating a supplemental intake of ~ 4 mg kg−1 d−1 of 20:4n-6

Compartmental analyses of 2H5-α-linolenic acid and C-U-eicosapentaenoic acid toward synthesis of plasma labeled 22:6n−3 in newborn term infants123

Background: During early postnatal development, the nervous system accretes docosahexaenoic acid (DHA; 22:6n−3), a highly unsaturated n−3 (omega-3) fatty acid (FA) used in the formation of neural cell membranes. DHA, which is present in human breast milk, may also be biosynthesized from n−3 FAs such as 18:3n−3 [α-linolenic acid (ALA)] or 20:5n−3 [eicosapentaenoic acid (EPA)]. An important concern is to what extent these precursors can supply DHA to the developing infant