Human ketone body production and utilization studied using tracer techniques: Regulation by free fatty acids, insulin, catecholamines, and thyroid hormones

1. The formation of acetoacetate, β-hydroxybutyrate and glucose was measured in the isolated perfused rat liver after addition of fatty acids. 2. The rates of ketone-body formation from ten fatty acids were approximately equal and independent of chain length (90–132μmol/h per g), with the exception of pentanoate, which reacted at one-third of this rate. The [β-hydroxybutyrate]/[acetoacetate] ratio in the perfusion medium was increased by long-chain fatty acids. 3. Glucose was formed from all odd-numbered fatty acids tested. 4. The rate of ketone-body formation in the livers of rats kept on a high-fat diet was up to 50% higher than in the livers of rats starved for 48h. In the livers of fat-fed rats almost all the O2 consumed was accounted for by the formation of ketone bodies. 5. The ketone-body concentration in the blood of fat-fed rats rose to 4–5mm and the [β-hydroxybutyrate]/[acetoacetate] ratio rose to 11.5. 6. When the activity of the microsomal mixed-function oxidase system, which can bring about ω-oxidation of fatty acids, was induced by treatment of the rat with phenobarbitone, there was no change in the ketone-body production from fatty acids, nor was there a production of glucose from even-numbered fatty acids. The latter would be expected if ω-oxidation occurred. Thus ω-oxidation did not play a significant role in the metabolism of fatty acids. 7. Arachidonate was almost quantitatively converted into ketone bodies and yielded no glucose, demonstrating that gluconeogenesis from poly-unsaturated fatty acids with an even number of carbon atoms does not occur. 8. The rates of ketogenesis from unsaturated fatty acids (sorbate, undecylenate, crotonate, vinylacetate) were similar to those from the corresponding saturated fatty acids. 9. Addition of oleate together with shorter-chain fatty acids gave only a slightly higher rate of ketone-body formation than oleate alone. 10. Glucose, lactate, fructose, glycerol and other known antiketogenic substances strongly inhibited endogenous ketogenesis but had no effects on the rate of ketone-body formation in the presence of 2mm-oleate. Thus the concentrations of free fatty acids and of other oxidizable substances in the liver are key factors determining the rate of ketogenesis.

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Relationship between plasma and muscle concentrations of ketone bodies and free fatty acids in fed, starved and alloxan-diabetic states

Biochemical Journal ◽

10.1042/bj1340499 ◽

1973 ◽

Vol 134 (2) ◽

pp. 499-506 ◽

Cited By ~ 22

Author(s):

Oliver E. Owen ◽

Helene Markus ◽

Stuart Sarshik ◽

Maria Mozzoli

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Free Fatty Acid ◽

Free Fatty Acids ◽

Plasma Glucose ◽

Ketone Body ◽

Ketone Bodies ◽

Water Concentration ◽

Diabetic Rats ◽

Muscle Membrane

1. Concentrations of ketone bodies, free fatty acids and chloride in fed, 24–120h-starved and alloxan-diabetic rats were determined in plasma and striated muscle. Plasma glucose concentrations were also measured in these groups of animals. 2. Intracellular metabolite concentrations were calculated by using chloride as an endogenous marker of extracellular space. 3. The mean intracellular ketone-body concentrations (±s.e.m.) were 0.17±0.02, 0.76±0.11 and 2.82±0.50μmol/ml of water in fed, 48h-starved and alloxan-diabetic rats, respectively. Mean (intracellular water concentration)/(plasma water concentration) ratios were 0.47, 0.30 and 0.32 in fed, 48h-starved and alloxan-diabetic rats respectively. The relationship between ketone-body concentrations in the plasma and intracellular compartments appeared to follow an asymptotic pattern. 4. Only intracellular 3-hydroxybutyrate concentrations rose during starvation whereas concentrations of both 3-hydroxybutyrate and acetoacetate were elevated in the alloxan-diabetic state. 5. During starvation plasma glucose concentrations were lowest at 48h, and increased with further starvation. 6. There was no significant difference in the muscle intracellular free fatty acid concentrations of fed, starved and alloxan-diabetic rats. Mean free fatty acid intramuscular concentrations (±s.e.m.) were 0.81±0.08, 0.98±0.21 and 0.91±0.10μmol/ml in fed, 48h-starved and alloxan-diabetic states. 7. The intracellular ketosis of starvation and the stability of free fatty acid intracellular concentrations suggests that neither muscle membrane permeability nor concentrations of free fatty acids per se are major factors in limiting ketone-body oxidation in these states.

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The development of the digestive system of the young animal. VI. The metabolism of short-chain fatty acids by the rumen and caecal wall of the young lamb

The Journal of Agricultural Science ◽

10.1017/s0021859600015458 ◽

1962 ◽

Vol 59 (3) ◽

pp. 375-379 ◽

Cited By ~ 14

Author(s):

D. M. Walker ◽

R. A. Simmonds

Keyword(s):

Fatty Acids ◽

Ketone Body ◽

Young Animal ◽

Marked Change ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Newborn Lamb ◽

Adult Sheep ◽

Body Production ◽

Chain Fatty Acids

1. Rumen and caecal wall tissues were taken at slaughter from lambs varying in age from newborn to 11 weeks. The ability of these tissues to metabolize the short-chain fatty acids, acetic, propionic and butyric acid was compared with tissues from adult sheep. Ketone body production was measured.2. The utilization of butyrate by the rumen wall in the newborn lamb was lower than in the adult, but exceeded the adult levels at 3 weeks of age and maintained this higher utilization to 11 weeks and probably longer. Ketone body production was negligible at birth but followed butyrate utilization closely thereafter.3. The caecal wall in the newborn lamb utilized butyrate at a much higher rate than the adult sheep tissue. Foetal lamb caecal tissue utilized butyrate to the same extent as in the newborn lamb. Levels were, however, typical of the adult within a day or two of birth and showed no subsequent effect of age. Ketone body production was negligible at all ages.4. Rumen development in milk-fed lambs slaughtered at 7 and 9 weeks of age was retarded anatomically and showed decreased capacity in the utilization of butyrate.5. The utilization of acetate and propionate by rumen and caecal tissues showed no marked change due to age. Ketone body production from these acids was low.

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Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men

British Journal Of Nutrition ◽

10.1017/s0007114510004472 ◽

2011 ◽

Vol 105 (6) ◽

pp. 857-865 ◽

Cited By ~ 30

Author(s):

Kyriakoula Marinou ◽

Martin Adiels ◽

Leanne Hodson ◽

Keith N. Frayn ◽

Fredrik Karpe ◽

...

Keyword(s):

Fatty Acids ◽

Young Women ◽

Metabolic Profile ◽

Ketone Body ◽

Ketone Bodies ◽

Young Men ◽

Isotopic Enrichment ◽

Plasma Nefa ◽

Lower Plasma Glucose ◽

Body Production

Before the menopause, women are relatively protected against CVD compared with men. The reasons for this sex difference are not completely understood, but hepatic fatty acid metabolism may play a role. The present study aimed to investigate the utilisation of plasma NEFA by the liver and to determine whether they are partitioned differently into ketone bodies and VLDL-TAG in healthy, lean young men and women. Volunteers were studied during a prolonged overnight fast (12–19 h) using an intravenous infusion of [U-13C]palmitate. After 12 h fasting, the women had a more advantageous metabolic profile with lower plasma glucose (P < 0·05) and TAG (P < 0·05) but higher plasma NEFA (P < 0·05) concentrations. Plasma 3-hydroxybutyrate (3-OHB) concentrations rose more in women than in men, and the transfer of13C from [U-13C]palmitate to plasma [13C]3-OHB reached a plateau 6–7 h after the start of the infusion in women but was still increasing at 6 h in men. This implies a slower 3-OHB production rate and/or dilution by other precursor pools in men. In women, the high isotopic enrichment of plasma 3-OHB suggested that systemic plasma fatty acids were the major source of 3-OHB production. However, in men, this was not observed during the course of the study (P < 0·01). There were no sex differences for the incorporation of13C into VLDL1- or VLDL2-TAG. The ability of young women to partition fatty acids towards ketone body production rather than VLDL-TAG may contribute to their more advantageous metabolic profile compared with young men.

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