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Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults



Background: Ketones are the brain's main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear. Objective: The aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8. Methods: In a crossover design, 9 participants with mean ± SD ages 34 ± 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and β-hydroxybutyrate (β-HB) analysis. Results: C8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol ⋅ h/L and 1876 ± 772 µmol ⋅ h/L, respectively); these values were 813% and 870% higher than CTL values ( P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses. Conclusions: In healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at as NCT 02679222.
Tricaprylin alone increases plasma ketone response more than coconut oil or other
medium chain triglycerides: an acute crossover study in healthy adults
Camille Vandenberghe1, 2, Valérie St-Pierre1, 2, Tyler Pierotti3, Mélanie Fortier1,
Christian-Alexandre Castellano1, Stephen C Cunnane1, 2,4
1Research Center on Aging, Sherbrooke, QC, Canada (CV, VSP, MF, CAC, SCC)
Departments of 2Pharmacology and Physiology, and 4Medicine, Université de
Sherbrooke, Sherbrooke, QC, Canada (CV, VSP, SCC)
3 Department of Biology-Health Sciences, Bishop’s University, Sherbrooke, QC, Canada
Author for correspondence: Stephen Cunnane
Research Center on Aging, 1036 Belvedere St. South, Sherbrooke, QC, Canada J1H 4C4
Tel: 1 819 780-2220, ext 45670;
Abbreviations: AcAc, acetoacetate; -HB, -hydroxybutyrate; FFA, free fatty acids;
CO, coconut oil; MCT, medium chain triglyceride; C8, tricaprylin; C10, tricaprin; AD,
Alzheimer’s disease.
Financial support: MCT were provided by Abitec Corporation, Columbus, USA.
Financial support from NSERC and Sojecci 2.
Trial Registration: NCT 02679222 on
Conflict of interest: The authors declare that they have no conflicts interest.
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Background: Ketones are the brain’s main alternative fuel to glucose. Dietary medium chain
triglyceride (MCT) supplements increase plasma ketones but their ketogenic efficacy relative to
coconut oil (CO) is not clear. Objective: To compare the acute ketogenic effect in healthy adults
of the following test oils: coconut oil (CO; 3% C8, 5% C10), classical MCT oil (C8/C10; 55%
C8, 35% C10), tricaprylin (>95% C8), tricaprin (>95% C10), or CO mixed 50:50 with C8/C10 or
C8. Design: In a crossover design, 7 men and 2 women of 34±12 y took two 20 mL doses of the
test oils prepared as an emulsion in 250 mL of lactose-free skim milk. During the control test
(CTL), participants received only the milk vehicle. The first test dose was taken with breakfast
and the second at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma
acetoacetate and β-hydroxybutyrate analysis. Results: C8 was the most ketogenic test oil with a
day-long mean of +295±155 µmol/L above CTL. C8 alone induced the highest plasma ketones
expressed as the areas-under-the-curve (AUC) for 0-4 h and 4-8 h; 780±426 µmol h/L and
1876±772 µmol h/L, respectively; these values were 813% and 870%, respectively, more than
CTL (P<0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The
acetoacetate/β-hydroxybutyrate ratio increased 56% more after CO than after C8 after both doses.
There was a significant positive correlation between the amount of C8 consumed and AUCs for
net change in plasma ketones ( =0.9, P=0.008 for both). Conclusion: In healthy adults, C8 alone
had the highest net ketogenic effect over 8 h, but induced only half the increase in acetoacetate/β-
hydroxybutyrate ratio compared to CO. Optimising the type of MCT may help in developing
ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with
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Keywords: Coconut oil, Medium chain triglycerides, Ketones, Tricaprylin, Tricaprin, Beta-
hydroxybutyrate, Acetoacetate
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The ketones, acetoacetate (AcAc) and β-hydroxybutyrate (β-HB), are the brain’s principal
alternative fuel to glucose under conditions when carbohydrate intake is significantly reduced, or
during fasting or strenuous aerobic exercise (1, 2). Ketones replace glucose and supply up to 80%
of the brain’s energy requirements during medically-supervised starvation of 40-60 days (3, 4).
The very high fat ketogenic diet has been used for many years to treat refractory childhood
epilepsy and increases plasma ketones by virtue of extreme carbohydrate restriction and
hypoinsulinemia (5).
An alternative means of moderately increasing ketones without radically altering food
intake or restricting carbohydrate is by consuming medium chain triglycerides (MCT; fatty acids
of 8-12 carbons) (2, 6-9). MCT induce mild to moderate ketonemia when added to a regular meal
because they are quickly absorbed via the portal vein and rapidly β-oxidized to acetyl-CoA in the
liver (2, 10). In contrast, common long chain dietary fatty acids are absorbed as chylomicrons via
the lymphatic system and distributed throughout the circulation before being metabolized. Unlike
long chain fatty acids, medium chain fatty acids do not need to be activated by carnitine in order
to access the inner mitochondrial membrane for β-oxidation (7).
MCT are typically purified from coconut oil (CO). To our knowledge, the ketogenic
effect of different MCT in humans has not been directly compared amongst themselves or to CO.
Therefore, we aimed to compare the acute ketogenic effect of CO to that of tricaprylin alone (C8
triglyceride), tricaprin alone (C10 triglyceride), a typical MCT mixture (C8/C10), or CO mixed
50:50 with C8/C10 or C8 alone. The 8 h metabolic study day protocol was designed to compare
the ketogenic effect of the dose of test oil taken with a meal (breakfast) to the same dose taken at
midday but without an accompanying meal.
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Ethical approval for this study was obtained from the Research Ethics Committee of the
Integrated University Health and Social Services of Eastern Townships – Sherbrooke University
Hospital Center, which oversees all human research done at the Research Center on Aging
(Sherbrooke, QC, Canada). All participants provided written informed consent prior to beginning
the study and were recruited from August to December 2015. They underwent a screening visit,
including the analysis of a blood sample collected after a 12 h overnight fast. Exclusion criteria
included smoking, diabetes or glucose intolerance (fasting glucose >6.1 mmol/L and glycosylated
hemoglobin >6.0%), strenuous aerobic exercise more than three times a week, CO allergy,
untreated hypertension, dyslipidemia, abnormal renal, liver, heart or thyroid function. This
project is registered on (NCT 02679222).
Test Oils
The composition of the CO (President’s Choice®, Toronto, ON, CAN) is shown in Table
1. The MCT oil was 55% C8, 35% C10 (Captex 355, Abitec, Columbus, OH, USA). The C8 oil
was 95% pure tricaprylin (Captex 8000, Abitec, Columbus, OH, USA). The C10 oil was 95%
pure tricaprin (Captex 1000, Abitec, Columbus, OH, USA). A 20 mL dose of each test oil was
mixed with 250 mL of lactose-free skim milk (Natrel®, Longueuil, QC, CAN) using a blender
(Magic Bullet©, Los Angeles, CA, USA). CO and C10 are solid at room temperature so they were
melted in a water bath at 60°C prior to blending into the milk base.
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Experimental design
The protocol involved seven separate but identical metabolic study days for each
participant, hence a repeated/longitudinal measurements design during which the test substances
were evaluated in random order: vehicle (CTL; 250 mL lactose-free skim milk) or 20 mL of the
test oils mixed with 250 mL of lactose-free skim milk (CO; C10; C8; C8/C10; CO + C8/C10
[50:50]; CO + C8 [50:50]) taken twice, once at breakfast and once at mid-day. Participants were
single blinded and crossed over from one treatment to the next during the trial course. The test
sequence was determined a priori by the investigator, and the participants were randomized to
sequences. On each metabolic study day, the participants arrived at 7:30 a.m. after a 12 h
overnight fast and a minimum of 24 h without alcohol intake. A forearm venous catheter was
installed and a baseline blood sample (Time 0) withdrawn. Participants then received a standard
breakfast during which they consumed the test beverage. The breakfast consisted of two pieces of
toast with raspberry jam, a piece of cheese, and two scrambled eggs. A second dose of the test
beverage was given alone for lunch, i.e. with no other food (Table 1). Water was available ad
libitum throughout the study day. Blood samples were taken as baseline (pre-dose) and every 30
min during 8 h with the first post-dose sample being taken 30 min after the test beverage was
consumed. Blood samples were centrifuged at 2846 g for 10 min at 4°C and plasma stored at -
80°C until analyzed.
Plasma metabolites analyses
Plasma -HB and AcAc were measured by an automated colorimetric assay as previously
described (9). Briefly, for AcAc, 25 L of plasma was mixed with 330 L of fresh reagent (Tris
buffer, pH 7.0, 100 mmol/L, 20 mmol/L sodium oxamate; 0.15 mmol/L NADH and 1U/mL -
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hydroxybutyrate dehydrogenase [ -HBDH]). For -HB, the reagent was Tris buffer (pH 9.0; 20
mM sodium oxamate, 1 mmol/L NAD, and 1U/mL -HBDH). Tris, oxamic acid, DL- -HB
sodium salt, Li-AcAc standard, and NAD were purchased from Sigma (St. Louis, MO, USA),
NADH, from Roche (Mannheim, Germany), and -HBDH from Toyobo (Osaka, Japan). The
change in absorbance at 340 nm between 15 and 120 s after the addition of the reagent was
measured on an automated clinical chemistry analyzer (Dimension Xpand Plus; Siemens,
Deerfield, IL, USA). The assay was calibrated with freshly diluted standards from frozen aliquots
of a 10 mmol/L standard of Li-AcAc or DL- -HB sodium salt, which is stable at -20°C for 2 and
6 months, respectively. Calibrations and quality controls were performed for each assay to ensure
the precision of the kits (coefficient of variation between tests 5 ± 1 %). Plasma glucose, lactate,
triglycerides, cholesterol, (Siemens Medical Solutions USA, Inc., Deerfield, IL, USA) and FFA
(Randox Laboratories Limited, West Virginia, USA) were analysed using commercial kits.
Glycated hemoglobin was measured by HPLC-723G7, a fully automated high performance liquid
chromatography instrument-reagent system (Tosoh Bioscience, King of Prussia, PA, USA).
Statistical analysis
All results are given as the mean ± SEM. The sample size calculation was based on a
previous study in which 8 participants were sufficient to measure a significant difference (β=
0.80) in plasma ketones after consuming 30 g of MCT oil (9) . We had n=9 for the present study
in case of a dropout during one of the seven tests. All statistical analyses were carried out using
SPSS 23.0 software (SPSS Inc., Chicago, IL, USA). Plasma ketone data are all reported in
relation to Time 0 (baseline). When plasma ketones are given in the plural, this refers to the total
of AcAc and β-HB combined. The second test dose was given 4 h after the first so the half-day
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periods are reported as 0-4 h and 4-8 h. For total ketones, the areas-under-the-curve (AUC) from
0-4 h and 4-8 h were calculated according the trapezoid method (11). Since the data were not
normally distributed (N<30), results of the seven tests were compared using Friedman’s test, and
the effect of the treatments as well as changes over time were determined in each group using
Wilcoxon’s signed rank test. False discovery rate (FDR) procedures for multiple comparisons
were used to control for incorrect rejection of the null hypothesis (12). Spearman correlations
were used to measure the statistical dependence between two variables. Differences were
considered statistically significant at P0.05. Graphs were prepared using Prism version 6.0
(GraphPad Software Inc., San Diego, CA, USA).
Seven men and two women (total of n=9) completed all the tests except for C10 (n=8;
Table 2). The participants’ baseline biochemical parameters corresponded to normal reference
values from the Sherbrooke University Hospital Center (Sherbrooke, QC) (9). No significant
gastrointestinal side effects were reported. There was no difference in plasma glucose, lactate,
triglycerides, or free fatty acid (FFA) response among the seven metabolic days (data not shown).
Plasma ketones
Compared to CTL, there was no difference in plasma ketones during the metabolic day on
which CO was evaluated (P=0.11; Figure 1). C10 alone significantly elevated plasma ketones up
to twofold between 5 and 6.5 h compared to CTL (P<0.01). Compared to the CTL, C8 alone
significantly increased plasma ketones by +288 ± 190 µmol/L above baseline at 0.5-1.5 h
(P<0.01), after which ketones returned to CTL values by 4 h. The second dose of C8 at midday
again significantly elevated plasma ketones compared to CTL, reaching a maximal peak
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concentration from 4.5 h to 6.5 h of +797 ± 285 µmol/L above baseline (P<0.01). Compared to
CTL, C8/C10 also induced a significant increase in ketones at 1 h (+250 ± 106 µmol/L above
baseline; P<0.01). In the second half of the metabolic day, C8/C10 significantly increased plasma
ketones from 4.5 to 7 h with a maximum of +646 ± 256 µmol/L above baseline (P<0.05). Both
CO + C8/C10 and CO + C8 produced intermediary effects on plasma total ketones that were
significantly higher than CTL at 0.5 and 1 h (+126 ± 55 µmol/L and +129 ± 113 µmol/L above
baseline; P<0.01) and significantly higher again at 5.5 and 6 h (respectively +341 ± 169 µmol/L
and +483 ± 206 µmol/L above baseline) in comparison with CTL (P<0.01; data not shown).
Mean ketones averaged over the whole metabolic study day were 5.3 times and 4.3 times higher
with C8 alone and C8/C10 alone than with CTL (P<0.05).
There was no difference in the plasma ketone AUC over the first 4 h period between CTL,
CO and C10 (P<0.12; Figure 2A). However, the AUC from 4-8 h of CO and C10 was
significantly higher than CTL (respectively, +88% and +171%; P<0.05). C8 alone induced the
highest plasma ketone 0-4 h AUC (780 ± 348 µmol h/L) and 4-8 h AUC (1876 ± 564 µmol h/L),
values that were 26% and 21% more than C8/C10 alone and, 813% and 870% more than CTL,
respectively (P<0.01). The two half-day AUCs (0-4 h and 4-8 h) were significantly different from
each other during all tests (P<0.05).
Plasma acetoacetate/
-hydroxybutyrate ratio
CO significantly increased the plasma AcAc/β-HB ratio compared to C8 from 0-4 h and
from 4-8 h (P<0.05; Figure 2B). AcAc/β-HB was also higher after C10 than after C8 during both
time periods (P<0.05). The 0-4 and 4-8 h AcAc/β-HB ratios on the CTL treatment were not
significantly different from those of any of the test oils (1.02 ± 0.50 for 0-4 h and 0.72 ± 0.27 for
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4-8 h; P>0.05). Plasma AcAc/β-HB ratios were significantly higher on CO + C8/C10 and on CO
+ C8 compared to C8 alone (P<0.01; Figure 2B). The ratio of AcAc/β-HB was significantly
higher during 0-4 h than during 4-8 h regardless of the test substance (P<0.05).
Plasma ketones versus dose of test oil
The 0-4 h and 4-8 h AUCs for the increase in plasma total ketones after C8 were
significantly positively correlated to the total dose of C8 given ( =0.9, P=0.008 and =0.9,
P=0.008, respectively; Figure 3A). Plasma total ketone AUCs after C10 were not significantly
correlated with the dose of C10 (P0.34, Figure 3B).
Our main observation is that C8 was the most ketogenic of the MCT tested (Figure 2A).
When C8 was mixed with CO in a 50:50 ratio, the combination dampened the net ketogenic
effect by 75 ± 27% compared to that of C8 alone. Hence the 5-10% medium chain fatty acid
content of CO was only sufficient to modestly stimulate ketone production and only without a
meal (4-8h in our study day). In contrast, when given alone, C8 induced a 3.4 fold higher total
plasma ketone daily mean response than CO alone (Figure 1). During the CTL test, total ketones
increased at 7-8 h due to low carbohydrate in the CTL beverage (vehicle for all the tests); this
increase during the CTL test was not different from that observed during the CO and C10 tests.
The significant positive correlation of medium chain fatty acid intake and plasma ketone
response was only observed for C8 (Figure 3A) but not for C10 (Figures 3B), suggesting that C8
drives the ketogenic effect of MCT containing a mixture of C8 and C10. C8 and C10 differ in
chain length by only two methylene groups, but C8 was clearly more ketogenic under our
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conditions. A family of medium chain fatty acyl-CoA dehydrogenases catalyzes the first step of
β-oxidation of C6-C12 fatty acids with a higher specific activity for C8 (13). As seen in
astrocytes in culture (14), C8 also appears to be preferentially β-oxidized over C10 in humans,
resulting in more rapid formation of acetyl-CoA, the substrate for ketogenesis. Although C10 is
not very ketogenic, it may have an indirect effect on brain fuel availability because it promotes
glycolysis and stimulates lactate release in isolated cultured astrocytes (14).
Nutritional state has an important effect on ketogenesis with fasting stimulating ketone
production more than the post-prandial state for any given load of C8 (15). Fatty acid synthesis is
generally decreased under fasting or very low food intake conditions in which acetyl-CoA
generation is unchanged or increased, which results in a bigger acetyl-CoA pool and increased
ketogenesis. This could explain the higher plasma ketone response during our 4-8 h study period
versus the 0-4 h period.
Despite its relatively poor ketogenic effect, CO induced a significantly higher AcAc/β-HB
ratio compared to C8 or C8/C10 (Figure 2B). During ketogenesis, β-HB and AcAc are exported
from the liver into the bloodstream for use by extrahepatic tissues such as the brain (16). It is
AcAc that is metabolized to CO2, so β-HB needs to undergo conversion to AcAc via β-HB
dehydrogenase before it can impact on ATP production (17). A higher AcAc/β-HB ratio could
therefore potentially favour more direct energy availability from ketones. However, it is not clear
that the AcAc/β-HB ratio observed in plasma represents the same ratio in mitochondria, so the
implications of a higher or lower plasma AcAc/β-HB ratio need further investigation.
Brain glucose uptake is lower in Alzheimer’s disease (AD) (2, 18). This problem develops
gradually before cognitive symptoms are present, continues as symptoms progress, and becomes
lower than the brain glucose hypometabolism occurring in normal aging (19, 20). In contrast to
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glucose, brain ketone uptake is similar in AD as in cognitively healthy age-matched controls (2,
18). For ketones to be a useful energy source in glucose-deprived parts of the AD brain, the
estimated mean daily plasma ketone concentration needs to be >200 µmol/L (21). With a total
one-day dose of 40 mL of C8, plasma ketones peaked at 900 µmol/L and the day-long mean was
363 ± 93 µmol/L, whereas on the same amount of CO, they peaked at 300 µmol/L and 107 ± 57
µmol/L, respectively. Our two dose test protocol (breakfast and midday) generated two peaks of
plasma total ketones throughout 8 h with the second dose inducing 3.5 and 2.4 times higher
ketones with C8 than CO, respectively. The first dose taken with a meal would be more typical
pattern but resulted in less ketosis that without a meal. One limitation of this study design is that
the metabolic study period was only 8 hours. A longer-term study lasting several weeks to
months would be useful to assess the impact of regular MCT supplementation on ketone
In summary, C8 was the most ketogenic MCT tested in this acute 8 h study and its
ketogenic effect was significantly higher in the absence of an accompanying meal. Despite a low
net ketogenic effect, CO may still be of interest because of its effect on plasma AcAc/β-HB ratio.
With the help of PET imaging and the ketone tracer, 11C-AcAc (2, 18, 20), it is now possible to
investigate the impact on tissue ketone uptake of various ketogenic interventions.
We thank our research nurses, Christine Brodeur-Dubreuil and Georgette Proulx, for their
assistance in participant screening, blood sampling and care of the participants.
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SCC, CAC and MF designed the study. CV, VSP and TP conducted the study. CV, VSP
and SCC analyzed and interpreted the data. All the authors read and approved the final version of
the paper.
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Table 1.
Test oils given on the metabolic study days
Composition (%) Quantity/dose (ml)
Coconut oil C8 C10 C8 C10
CTL 0 0 0 0 0
CO 100 0 0 0.6 1
C8/C10 0 60 40 12 8
CO + C8/C10 50 30 20 6.3 4.5
CO + C8 50 50 0 10.3 0.5
C8 0 100 0 20 0
C10 0 0 100 0 20
CO, coconut oil; CTL, control; C8, tricaprylin; C10, tricaprin
CO fatty acid composition (%): C8:0, 3; C10:0, 5; C12:0, 45; C14:0, 18;
C16:0, 15; C18:0, 7; C18:1, 7
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Table 2.
Baseline demographic and biochemical parameters of the participants
Age (y) 34
Weight (kg) 72
Height (cm) 175
Body mass index (kg/m
) 24
Plasma metabolites
Glucose (mmol/L) 4.3
Ketones (µmol/L) 90
Glycated hemoglobin (%) 5.2
Total cholesterol (mmol/L) 4.3
Triacylglycerol (mmol/L) 0.7
Values are mean ± SD, n=9
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Figure Legends
Figure 1. Plasma concentration and summed daily means (far right) during the metabolic study
days for total ketones (β-hydroxybutyrate and acetoacetate) obtained without an added test oil
(CTL, ), or after taking two 20 mL doses of coconut oil alone (CO, ), tricaprin alone (C10, ),
medium chain triglyceride (C8/C10, ), or tricaprylin alone (C8, ). Empty arrow indicates when
breakfast plus test oil were consumed; full arrow indicates when test oil alone was consumed
without an accompanying meal at midday. Data for metabolic study days on which CO+C8/C10
and CO+C8 were tested are not shown here for clarity but their area-under-the-curve data are
shown in Figure 2. Values are presented as mean ± SEM for n = 9/point. * Different from CTL,
P< 0.05.
Figure 2. Plasma concentration and summed means of 0-4 h and 4-8 h areas-under-the-curve
(AUC) for plasma total ketones, i.e. acetoacetate and β-hydroxybutyrate combined [A], and for
the mean acetoacetate/β-hydroxybutyrate ratio [B]. Bars represent: no test oil consumed (CTL),
or after taking two doses of coconut oil alone (CO), tricaprin alone (C10), medium chain
triglyceride (C8/C10), tricaprylin alone (C8), CO+C8/C10 (50:50), or CO+C8 (50:50). Bars are
the mean ± SEM for n = 9. The 0-4 h AUC was significantly different from the 4-8 h AUC under
all conditions. a<b<c<d<e and A<B<C<D<E: labeled means without a common letter differ,
Figure 3. Direct, linear relation between the 0-4 h ( ) or 4-8 h ( -- ) areas-under-the-curve
for plasma total ketones in relation to the dose of tricaprylin (C8; A) or tricaprin (C10; B)
consumed. Values are the mean ± SEM for n = 9/point; P<0.05.
Current Developments in Nutrition
DOI: 10.3945/cdn.116.000257
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Current Developments in Nutrition
DOI: 10.3945/cdn.116.000257
... Medium-chain triglyceride (MCT) oil is one such ketogenic supplement that has been demonstrated to elevate blood βHB to levels achieved in mild ketosis. MCTs are defined as fatty acids that are between 6 and 10 carbons in length (C 12 can be characterized as a medium-or longer chain fatty acid), with C 8 having the greatest ketogenic effect [12]. Upon consumption, MCTs are absorbed quickly and the liberated fatty acids are either oxidized in the liver for energy or metabolized into βHB by the liver such that circulating βHB increases. ...
... Medium-chain triglyceride (MCT) oil is one such ketogenic supplement that has been demonstrated to elevate blood βHB to levels achieved in mild ketosis. MCTs are defined as fatty acids that are between 6 and 10 carbons in length (C 12 can be characterized as a medium-or longer chain fatty acid), with C 8 having the greatest ketogenic effect [12]. Upon consumption, MCTs are absorbed quickly and the liberated fatty acids are either oxidized in the liver for energy or metabolized into βHB by the liver such that circulating βHB increases. ...
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Chronic, low-grade inflammation is associated with the development of numerous diseases and is mediated in part by overactivation of the NLRP3 inflammasome. The ketone body beta-hydroxybutyrate (βHB) suppresses the NLRP3 inflammasome and alters intracellular signalling pathways in vitro and in animal models; however, this effect has not yet been shown in vivo in humans. The purpose of this single-arm pilot trial was to determine if consuming 15 mL of C8 medium-chain triglyceride (trioctanoin; MCT) oil, which induces mild elevation of βHB, twice daily (30 mL total) for 14 days would suppress markers of NLRP3 inflammasome activation in young, healthy humans while following their habitual diet. Consuming a single dose of 15 mL of C8 MCT oil significantly raised blood βHB from fasting at 60 minutes and 120 minutes post ingestion (both P < 0.05 ). However, consumption of C8 MCT oil for 14 days did not impact markers of monocyte NLRP3 inflammasome activation compared to baseline. Specifically, caspase-1 activation and secretion of its downstream product interleukin (IL)-1β were unchanged following 14 days of C8 MCT oil supplementation when measured in unstimulated and LPS-stimulated whole blood cultures (all P > 0.05 ). Acetylation of histone H3 on the lysine residue 9 was unchanged ( P < 0.05 ) and acetylation of lysine residue 14 was decreased ( P < 0.05 ) following 14 days of supplementation. Thus, adding twice daily C8 MCT oil supplementation to the habitual diet of young, healthy humans does not appear to suppress NLRP3 inflammasome activation.
... The greatest ketogenic MCFA exist in palm kernel oil or coconut oil which are caprylic acid (C8) and capric acid (C10) [11]. Nonetheless, due to the low concentration of lipids in coconut oils, such interventions only increase ketone body levels partially [106]. For that reason, various products with greater levels of caprylic and capric acid have been established [107]. ...
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Migraine is a prevalent heterogeneous neurological disorder, enumerated as the eighth most disabling neurological disorder by the World Health Organization. The growing advancement in technology and investigation of various facets of cerebral metabolism in migraine has shed light to metabolic mechanisms in migraine pathophysiology. A growing number of clinical research postulates migraine as a reaction to oxidative stress levels that go beyond antioxidant capacity or cerebral energy deficiency. This has become an extremely attractive subject area and over the past years there has also been a sustained research activity in using ketone bodies (KB) as a novel potential migraine prophylaxis. Not much epidemiological research has been conducted to exhibit the efficacy of ketone bodies in abnormal metabolism in migraine pathophysiology. Therefore, a better understanding of ketone bodies in metabolic migraine may provide novel therapeutic opportunities. The goal of this review is to assess present understanding on potential migraine triggers, as well as how ketogenic interventions support metabolic disability in migraines and address the therapeutic importance of ketones in migraine treatment, accenting clinical studies (including neuroimaging and therapeutic studies). This review is intended to demonstrate existing literature on the effects of ketone bodies on metabolic migraine traits to guide the readership through current concepts and foster a perspective for future research.
... Medium chain triglycerides oil is extracted from coconut and/or palm oil and can be used as a dietary supplement to induce mild ketosis (~ 0.5 mM) (71,72). Although MCTs containing high levels of tricaprylin (C8) are more ketogenic than with other compositions, the peak BHB concentration never reaches 1 mM with tolerable doses of MCTs (73). Compared to ketogenic diets, intake of MCTs has the advantage of inducing ketosis acutely, whereas ketogenic diets must be followed for at least several days to achieve ketosis. ...
Background: Ketone bodies have been proposed as an "energy rescue" for the Alzheimer's disease (AD) brain, which underutilizes glucose. Prior research has shown that oral ketone monoester (KME) safely induces robust ketosis in humans and has demonstrated cognitive-enhancing and pathology-reducing properties in animal models of AD. However, human evidence that KME may enhance brain ketone metabolism, improve cognitive performance and engage AD pathogenic cascades is scarce. Objectives: To investigate the effects of ketone monoester (KME) on brain metabolism, cognitive performance and AD pathogenic cascades in cognitively normal older adults with metabolic syndrome and therefore at higher risk for AD. Design: Double-blinded randomized placebo-controlled clinical trial. Setting: Clinical Unit of the National Institute on Aging, Baltimore, US. Participants: Fifty cognitively intact adults ≥ 55 years old, with metabolic syndrome. Intervention: Drinks containing 25 g of KME or isocaloric placebo consumed three times daily for 28 days. Outcomes: Primary: concentration of beta-hydroxybutyrate (BHB) in precuneus measured with Magnetic Resonance Spectroscopy (MRS). Exploratory: plasma and urine BHB, multiple brain and muscle metabolites detected with MRS, cognition assessed with the PACC and NIH toolbox, biomarkers of AD and metabolic mediators in plasma extracellular vesicles, and stool microbiome. Discussion: This is the first study to investigate the AD-biomarker and cognitive effects of KME in humans. Ketone monoester is safe, tolerable, induces robust ketosis, and animal studies indicate that it can modify AD pathology. By conducting a study of KME in a population at risk for AD, we hope to bridge the existing gap between pre-clinical evidence and the potential for brain-metabolic, pro-cognitive, and anti-Alzheimer's effects in humans.
... Based on the above data and other recent findings, the nonlinear relationship between MCT intake and plasma ketone concentration might begin at a relatively low dose of MCTs (6 g of C8 + 4 g of C10 vs. 12 g of C8 + 8 g of C10) [ (7) (F1A)]. Based on the results of several studies (7,8,18), it is clear that 20 g of C8 produces a significantly stronger (but perhaps not twice as high) [(7) (D2)] ketogenic response than 10 g of C8. Further studies are required to determine whether doses higher than 20 g can produce a significantly larger ketogenic response and/or a greater risk of unwanted side effects. ...
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Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose–response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15–20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.
... Their consumption, especially at high doses, can be associated with mild gastrointestinal issues in some patients, but they are usually transitory and can be tempered by dose titration (139) . Certain dietary patterns including intermittent fasting, time-restricted feeding (149) , energetic restriction (29) and even coconut oil (150,151) do not necessarily raise blood ketones, so their clinical and physiological implications fall outside the scope of this report. ...
Alzheimer’s disease (AD) is the most common major neurocognitive disorder of aging. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) - to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.
... Exclusion criteria were weight <50 kg, current smoking, diagnosed diabetes (type 1 or 2), history of heart disease, history of disease related to internal organs or metabolism, experience of "sensitive gut" or known intolerance to coconut oil or sunflower oil, medication expected to affect glucose-or lipidmetabolism, fasting during the study or one month before, high intensity physical activity more than 3 days/week, dementia, severe psychiatric conditions, Hb < 125 g/L, and participation in a lifestyle intervention during the last 6 months. The sample size was estimated to be sufficient to detect differences of clinical significance for our primary outcome (BHB) with a power of 80 % and alpha = 0.05, based on effect sizes reported in previous studies (Vandenberghe et al., 2017). For the current sub-study, no reference was available to estimate what would constitute a meaningful or expected effect size for changes in BDNF, and the analyses should therefore be considered exploratory. ...
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Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC). Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65–75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0–2 h to changes in BDNF at 0–4 h). ICC estimates were calculated from baseline levels from the three study days. Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07–0.44; p = 0.007). Individual change in BHB 0–2 h, predicted change in proBDNF 0–4 h, (β = 0.40, CI 0.12–0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0–2 h (β = −0.88, CI −1.37 to −0.40; p < 0.001) and cumulatively 0–4 h (β = −1.01, CI −1.75 to −0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92–0.99) for proBDNF, and 0.72 (CI 0.47–0.89) for mBDNF. Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health. Clinical Trial Registration: , NCT03904433.
... The differences most of all concern the fatty acid composition of the chows, inducing changes in the tissue fatty acid content, which we reported in detail previously (Liśkiewicz et al., 2021). As an example, the plant-based diet delivers a high amount of caprylic acid (Liśkiewicz et al., 2021), which is often referred to as the "most ketogenic MCT (Medium Chain Triglycerides)" due to its rapid breakdown from an 8carbon fatty acid to ketone bodies (Vandenberghe et al., 2017). Secondly, we observe slightly higher levels of blood ketone level in the plant fat-based diet in comparison to the animal fat-based diet in our experiments (although no significant differences were noted in the measurements performed in this experiment). ...
Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.
This chapter describes the constituents and health benefits of the major foods and food groups in the Med diet. It also describes possible ways in which these foods may benefit health and implications for how best to implement a Med diet. Extra virgin olive oil (EVOO) is produced by crushing olives, and since olives are the fruit of the tree, EVOO is essentially a fruit juice. Olive oil is the food that most differentiates the Med diet from other healthy eating patterns. Suboptimal intake of fruit and vegetables ranks amongst the top dietary contributors to the global burden of disease and premature death. Pulses are legumes that are usually dried, whereas ‘legume’ is a broader term that also includes green peas and green beans. Mediterranean tree nuts include walnuts, almonds, hazelnuts, pine nuts and pistachios. Sunflower and pumpkin seeds are popular aperitif foods in many Mediterranean countries.
Life expectancy has been increasing globally along with the risk of developing Alzheimer’s or other dementias. Diets high in saturated fats, refined sugars and a sedentary lifestyle are determining factors in the development of a metabolic syndrome. These factors induce energy imbalance and dysfunctional brain metabolism, hence increasing the risk of cognitive impairment and/or dementia. A cohort study with mild cognitive impairment found that it was found that the presence of three or more components of a metabolic syndrome increased the risk of Alzheimer’s. On the other hand, hyperglycemia induces glutamate excitotoxicity in neurons, β-amyloid accumulation, tau phosphorylation and oxidative stress. The present chapter will cover the dysregulation of brain metabolism during physiological and pathological aging, and how metabolic challenges such fasting, caloric restriction and ketogenic diet reverts many of the deleterious effects of brain aging, favoring energy balance and cognitive function.
Brain glucose uptake has long been recognized to be reduced in Alzheimer’s disease (AD) but was mainly assumed to be a consequence of reduced neuronal activity. More recently, several studies challenged this concept by showing that brain glucose hypometabolism was also present in individuals at high risk for AD before the presence of any cognitive symptoms. Thus, it is of great interest to know whether cognitive decline can be prevented or delayed if the glucose metabolism defect is at least partly corrected or bypassed. The ketones β‎-hydroxybutyrate and acetoacetate are the brain’s main alternative fuel to glucose, and their uptake in mild cognitive impairment (MCI) and mild to moderate AD is similar to that seen in healthy age-matched controls. Based on these findings, it is conceivable that ketones could be used to help rescue brain fuel supply during aging. Evidence from published clinical trials showed that increasing ketone availability to the brain via nutritional ketosis can have a beneficial effect on brain energy metabolism and cognitive outcomes in both MCI and mild to moderate AD. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or ketogenic supplements, such as medium-chain triglycerides containing the eight- and ten-carbon fatty acids, octanoate and decanoate. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies aimed at AD, it seems reasonable that consideration be given to correcting the underlying problem of deteriorating brain glucose uptake observed with aging.
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Short- and medium-chain fatty acids (SCFAs and MCFAs), independently of their cellular signalling functions, are important substrates of the energy metabolism and anabolic processes in mammals. SCFAs are mostly generated by colonic bacteria and are predominantly metabolized by enterocytes and liver, whereas MCFAs arise mostly from dietary triglycerides, among them milk and dairy products. A common feature of SCFAs and MCFAs is their carnitine-independent uptake and intramitochondrial activation to acyl-thioesters. Contrary to long-chain fatty acids, the cellular metabolism of SCFAs and MCFAs depends in a lesser extent on fatty acid-binding proteins. SCFAs and MCFAs modulate tissue metabolism of carbohydrates and lipids as manifested by mostly inhibitory effect on glycolysis and stimulation of lipogenesis or gluconeogenesis. SCFAs and MCFAs exert in mitochondria no or only weak protonophoric and lytic activities and do not significantly impair the electron transport in the respiratory chain. SCFAs and MCFAs modulate mitochondrial energy production by two mechanism: they provide reducing equivalents to the respiratory chain and partly decrease efficacy of the oxidative ATP synthesis.
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Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Kei Sakamoto, Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.
Ketone bodies β-hydroxybutyrate (BHB) and acetoacetate are important metabolic substrates for energy production during prolonged fasting. However, BHB also has signaling functions. Through several metabolic pathways or processes, BHB modulates nutrient utilization and energy expenditure. These findings suggest that BHB is not solely a metabolic intermediate, but also acts as a signal to regulate metabolism and maintain energy homeostasis during nutrient deprivation. We briefly summarize the metabolism and emerging physiological functions of ketone bodies and highlight the potential role for BHB as a signaling molecule in starvation response.
Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed.
Background: The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and β-hydroxybutyrate, are the brain's main alternative energy substrates to glucose. Objective: To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). Methods: Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. Results: ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 μmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. Conclusion: Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.
Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized, and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is non-invasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
Objective: In humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2) ¹³C-β-hydroxybutyrate and ¹³C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism. Methods: Eight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation. Using isotope ratio mass spectroscopy, ¹³C-D-β-hydroxybutyrate and ¹³C-trioctanoate β-oxidation to ¹³CO₂ was measured over 12 h on the pre- and post-MCT metabolic study days. Results: On the post-MCT metabolic study day, plasma ketones (β-hydroxybutyrate plus acetoacetate) peaked at 476 μM, with a mean value throughout the study day of 290 μM. Post-MCT, ¹³C-trioctanoate β-oxidation was significantly lower 1 to 8 h later but higher 10 to 12 h later. MCT supplementation did not significantly alter ¹³C-D-β-hydroxybutyrate oxidation. Conclusions: This MCT supplementation protocol was mildly and safely ketogenic and had no side effects in healthy humans on their regular diet. This degree of ketonemia is estimated to contribute up to 8% to 9% of brain energy metabolism.
The area under the curve (AUC) of the concentration–time curve for a drug or metabolite, and the variation associated with the AUC, are primary results of most pharmacokinetic (PK) studies. In nonclinical PK studies, it is often the case that experimental units contribute data for only a single time point. In such cases, it is straightforward to apply noncompartmental methods to determine an estimate of the AUC. In this report, we investigate noncompartmental estimation of the AUC using the log-trapezoidal rule during the elimination phase of the concentration–time profile, and we account for the underlying distribution of data at each sampling time. For data that follow a normal distribution, the log-trapezoidal rule is applied to arithmetic means at each time point of the elimination phase of the concentration–time profile. For data that follow a lognormal distribution, as is common with PK data, the log-trapezoidal rule is applied to geometric means at each time point during elimination. Since the log-trapezoidal rule incorporates nonlinear combinations of mean concentrations at each sampling time, obtaining an estimate of the corresponding variation about theAUC is not straightforward. Estimation of this variance is further complicated by the occurrence of lognormal data. First-order approximations to the variance of AUC estimates are derived under the assumptions of normality, and lognormality, of concentrations at each sampling time. AUC estimates and variance approximations are utilized to form confidence intervals. Accuracies of confidence intervals are tested using simulation studies.
Medium-chain fatty acids (MCFAs) comprise saturated fatty acids with 6–10 carbons. Besides synthetic medium-chain triglyceride (MCT) oils there are natural sources, like coconut oil and dairy fat. Compared with long-chain fatty acids (LCFAs), the chemical and physical properties of MCFAs show substantial metabolic differences. MCFAs do not require binding to proteins such as fatty-acid binding protein, fatty acid transport protein, and/or fatty acid translocase (FAT, homolog to human platelet CD36). MCFAs are a preferred source of energy (β-oxidation). MCFAs are also incorporated into adipose tissue triglycerides, and may influence adipose tissue and other systemic functions more substantially than previously assumed. MCTs reduce fat mass, through down-regulation of adipogenic genes as well as peroxisome proliferator activated receptor-γ. Recent studies confirmed the potential of MCFAs to reduce body weight and particularly body fat. This effect was not transient. MCFAs reduce lipoprotein secretion and attenuate postprandial triglyceride response. It was, however, frequently observed that MCTs increase fasting cholesterol and triglyceride levels. But, given in moderate amounts, in diets with moderate fat supply, MCFAs may actually reduce fasting lipid levels more than oils rich in mono- or polyunsaturated fatty acids. The same is true for glucose levels. MCTs improved several features contributing to enhanced insulin sensitivity. Under certain in vitro conditions, MCTs exert proinflammatory effects, but in vivo MCTs may reduce intestinal injury and protect from hepatotoxicity.