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Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis/ lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of two doses of caffeine in healthy adults (2.5; 5.0 mg/kg) during a 4-hour metabolic study period. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined. NCT 02694601.
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1
Caffeine intake increases plasma ketones: an acute metabolic study in humans
Camille Vandenberghe
1, 2
, Valérie St-Pierre
1, 2
, Alexandre Courchesne-Loyer
1, 2
, Marie
Hennebelle
1
, Christian-Alexandre Castellano
1
, Stephen C Cunnane
1, 2,3
1
Research Center on Aging, Sherbrooke, CIUSSS de l’Estrie – CHUS, QC, Canada (CV, VSP,
ACL, MH, CAC, SCC)
2
Department of Pharmacology & Physiology, Université de Sherbrooke, Sherbrooke, QC,
Canada (CV, VSP, ACL, SCC)
3
Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada (SCC)
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;
Stephen.Cunnane@USherbrooke.ca
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ABSTRACT
Brain glucose uptake declines during aging and is significantly impaired in Alzheimer’s disease. Ketones
are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the
brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on
lipolysis/ lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate
the acute ketogenic effect of two doses of caffeine in healthy adults (2.5; 5.0 mg/kg) during a 4-hour
metabolic study period. Caffeine given at breakfast significantly stimulated ketone production in a dose-
dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-
term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be
determined.
Key words: Ketones; Ketonemia; Caffeine; Free fatty acids; Medium chain triglycerides; Lipolysis;
Alzheimer’s disease.
RÉSUMÉ
La consommation cérébrale de glucose diminue avec l’âge et, tout particulièrement, avec la maladie
d’Alzheimer. L’élaboration de différentes stratégies nutritionnelles pour optimiser la production de cétones,
le principal carburant alternatif cérébral, est nécessaire afin de soutenir les besoins énergétiques du
cerveau vieillissant. La caféine est une molécule d’intérêt en raison de son action sur le métabolisme
lipidique. L’effet aigu de différentes doses de caféine (2.5; 5.0 mg/kg) sur la production de cétones était
évalué chez dix sujets. Nos résultats ont montré que la caféine ajoutée à un repas stimule
significativement la cétonémie à des concentrations comparables à un jeûne de 12h et cette réponse est
dose-dépendante (+88 à +116%). Ainsi, la prise de caféine combinée avec une source alimentaire
cétogène comme les triglycérides à chaine moyenne dans le but de maximiser la cétonémie constitue une
piste prometteuse d’intervention en concomitance avec d’autres traitements thérapeutiques dans un
contexte de maladies neurodégénératives.
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INTRODUCTION
1
2
Caffeine upregulates metabolic rate (Miller et al. 1974), and stimulates energy expenditure. It is an
3
adenosine receptor antagonist that increases sympathetic activity (Bellet et al. 1969) and inhibits cyclic
4
nucleotide phosphodiesterase, which is responsible for catalyzing the conversion of cyclic adenosine
5
monophosphate (cAMP) to AMP (Butcher et al. 1968; Quan et al. 2013). As a result, higher tissue
6
concentrations of cAMP activate hormone-sensitive lipase and promote lipolysis (Acheson et al. 2004;
7
Butcher et al. 1968). Free fatty acids (FFA) are the product of lipolysis and can be used as an immediate
8
source of energy by many organs. They can also be converted by the liver into ketones (acetoacetate
9
[AcAc], β-hydroxybutyrate [β-HB] and acetone). Most organs use glucose and FFA as energy substrates.
10
However, the brain is unable to use FFA for energy, and requires ketones as the principal alternative fuel
11
to glucose (Cunnane et al. 2016). Plasma ketones are highly positively correlated to their utilization by the
12
brain (Cunnane et al. 2016; Mitchell et al. 1995) and can provide up to 70% of brain’s total energy during
13
period of hypoglycaemia as, for example, during fasting (Owen et al. 1967).
14
15
Brain glucose uptake is 10-15% lower during normal aging (Nugent et al. 2014), and can be up to 35%
16
lower in certain brain regions in neurodegenerative diseases such as Alzheimer’s disease (AD)
17
(Castellano et al. 2015). Several studies suggest that brain glucose hypometabolism potentially
18
contributes to the onset and/or progression of AD (Cunnane et al. 2016; Mosconi et al. 2005; Nugent et al.
19
2014; Reiman et al. 2004; Schöll et al. 2011). A ketogenic supplement could therefore potentially help
20
support the brain’s energy needs during aging. Hence, the primary aim of this study was to evaluate
21
whether the lipolytic effect of caffeine acutely increases plasma ketones in healthy adults during a four-
22
hour metabolic study period. The secondary aim was to confirm whether caffeine increases FFA as
23
previously reported (Acheson et al. 1980; Acheson et al. 2004).
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PARTICIPANTS AND METHODS
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27
Participants
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Ethical approval for this study was obtained from the Research Ethics Committee of the Integrated
29
University Health and Social Services of the Eastern Townships – Sherbrooke University Hospital Center,
30
which oversees all human research done at the Research Center on Aging (Sherbrooke, QC, Canada). All
31
participants provided written informed consent prior to beginning the study. They underwent a screening
32
visit, including the analysis of a blood sample collected after a 12 h overnight fast. Exclusion criteria
33
included regular high consumption of caffeine (>300 mg/day), smoking, diabetes or glucose intolerance
34
(fasting glucose >6.1 mmol/L and glycosylated hemoglobin >6.0%), untreated hypertension, dyslipidemia,
35
abnormal renal, liver, heart or thyroid function. This project is registered on ClinicalTrials.gov (NCT
36
02694601).
37
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Experimental design
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The protocol involved three randomized four-hour metabolic study days: a baseline metabolic day (CTL)
40
and two days each with a different dose of caffeine (2.5 mg/kg [C-2.5] and 5.0 mg/kg [C-5.0]). On each
41
metabolic study day, the participants arrived at 8:00 a.m. after 12 h of fasting and 24 h without caffeine
42
intake. At the time of signing the consent form, participants were aware of the 12 h fast and to abstain
43
from consuming caffeine. They also received a reminder call 24 h before the metabolic study day. A
44
forearm venous catheter was installed and blood samples were taken every 30 min during 4 hours. After
45
installing the catheter and the first blood sample, participants received a standard breakfast comprised of
46
two pieces of toast with raspberry jam, a piece of cheese, applesauce and 100 ml of juice. The breakfast
47
contained 85 grams of carbohydrate, 9.5 g of fat and 14 g of protein. Commercially available caffeine
48
tablets (200 mg extra-strength Life Brand
, ON, Canada) were hand crushed to powder and two doses
49
were provided (2.5 mg/kg and 5.0 mg/kg) on separate test days. The low dose corresponding to 1½ cup of
50
coffee and the high dose to 3 cups of regular coffee, the highest quantity recommended by Heath
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Canada. The caffeine dose to be given was mixed in 104 ml of applesauce and consumed during
52
breakfast. No caffeine was added to the breakfast for CTL. Water was available ad libitum throughout the
53
study day. Blood samples were centrifuged at 3500 rpm for 10 min at 4°C and plasma was stored at -80°C
54
until further analysis.
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56
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Plasma analyses
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Caffeine
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Plasma caffeine was measured using a complete ELISA Kits from Neogen (WI, USA), according to the
60
manufacturers’ protocol with the following modifications. Caffeine (Sigma-Aldrich
®
, St-Louis, Mo, USA)
61
was diluted with the Neogen kit buffer (EIA) at multiple dilutions ending with the standard curve dilutions
62
from 0 to 25 ng/ml. Plasma samples were then diluted with EIA buffer at a 1:50 000 dilution. Both
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standards and samples were run in duplicate. The absorbance was then measured with a plate reader
64
(VICTOR, Perkin Elmer Inc, MA, USA) at 690 nm.
65
66
Metabolites
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Plasma glucose, lactate, triglycerides, total cholesterol (Siemens Medical Solutions USA, Inc., Deerfield,
68
IL, USA) and free fatty acids (Randox Laboratories Ldt, West Virginia, USA) were measured using
69
commercial kits on a clinical biochemistry analyzer (Dimension Xpand Plus, Siemens Healthcare
70
Diagnosis Inc., Deerfield, IL, USA) as previously described (Courchesne-Loyer et al. 2013). Plasma β-HB
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and AcAc were evaluated by an automated colorimetric assay as previously described (Courchesne-Loyer
72
et al. 2013).
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Statistical analysis
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All results are given as mean ± SEM. Ten participants were sufficient to meet the statistical power
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(β=0.80) needed to observe a significant difference in plasma FFA with the caffeine supplementation
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(Acheson et al. 1980). For lactate, metabolic study day values were normalized to baseline in order to
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account for variability at the beginning of the study day. For post-caffeine ketone and FFA analysis, the
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area under the curve (AUC) was calculated from 2 to 4-hour post-dose because that was when maximal
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plasma caffeine was achieved. All statistical analyses were carried out using SPSS 23.0 software (SPSS
81
Inc., Chicago, IL, USA). Comparison of the three test conditions was done using the Friedman test, and
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the effect of caffeine supplementation was determined in each group using a Wilcoxon’s signed rank test.
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Differences were considered statistically significant at p≤0.05. Data were graphed using Prism version 6.0
84
(GraphPad Software Inc., San Diego, CA, USA).
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RESULTS
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Two men and eight women completed all three test conditions (Table 1). Participants were 33 ± 19 years
88
of age and had a body mass index of 24 ± 8 (n=10). The participant’s baseline biochemical parameters
89
corresponded to normal references values from the Sherbrooke University Hospital Center (Sherbrooke,
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Qc). No significant side effects were reported following caffeine intake. Baseline plasma caffeine values
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did not significantly differ from zero on any of the three study days (Fig.1). There was no difference in
92
plasma glucose, triglycerides, or cholesterol response across the three metabolic days (data not shown).
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Plasma lactate differed across the three metabolic days (p=0.045), but after normalizing the data to
94
baseline, these differences disappeared (p=0.607).
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A dose-response was observed for plasma caffeine across the three metabolic days (p<0.05; Fig. 1).
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Plasma caffeine significantly increased during the first hour post-dose (p<0.05). C-2.5 increased plasma
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caffeine to a maximum of 7.5 ± 1.5 mg/L at 2 h and C-5.0 increased plasma caffeine to a maximum of
99
10.0 ± 2.3 mg/L at 3 h (p<0.05). No difference in plasma AcAc levels was observed across the three test
100
days (p=0.497; Fig 2A, 2C). However, after normalizing the data to baseline, there was a significant group
101
difference between baseline and the two doses of caffeine at 3.5 h, at which time AcAc was significantly
102
increased (p<0.05; data not shown). A group difference was observed for the β-HB response from 2 to 4 h
103
post-dose (p<0.05; Fig. 2B and 2D). Caffeine increased plasma β-HB by 88% and 116% in a dose-
104
dependent manner (p<0.05). No significant difference in plasma FFA was observed during 0-2 h post-
105
dose (Fig. 3A). Globally, FFA decreased from 711 ± 398 µM to 91 ± 42 µM during this period (Fig. 3A).
106
Between 2 – 4 h after the breakfast, a dose-related increase of FFA was observed with the two doses of
107
caffeine (p<0.005; Fig. 3B). C-2.5 raised plasma FFA concentrations to 548 ± 276 µM after 4 h whereas
108
C-5.0 raised plasma FFA to 695 ± 433 µM.
109
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DISCUSSION
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This short-term study showed that caffeine intake can stimulate ketogenesis by increasing β-HB
113
concentrations by 88-116% with a maximum within four hours post-dose. A dose-response was observed
114
for plasma β-HB (Fig. 2D) but not for AcAc (Fig. 2C), which could be explained by the larger inter-group
115
variation in AcAc. The increase in plasma ketones obtained with these doses of caffeine could at least
116
transiently contribute to 5-6% of brain energy needs (Cunnane et al. 2016).
117
The increased plasma FFA after caffeine seen in the present study confirms prior results (Acheson et al.
118
1980; Acheson et al. 2004; Bellet et al. 1968; Bellet et al. 1969). Caffeine competes for the adenosine
119
receptor, inhibits phosphodiesterase activity and increases plasma FFA. FFA entering the liver are beta-
120
oxidized and converted to ketones due to condensation of pairs of acetyl-CoA units as their availability
121
exceeds their utilization by the tricarboxylic acid cycle (Wang et al. 2014).
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The increase in blood ketones shown here was equivalent to that observed after an overnight fast.
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Another way of increasing blood ketones is to provide a source of medium-chain triglyceride (MCT)
125
(Courchesne-Loyer et al. 2013). Caffeine combined with an MCT supplement could potentially prolong
126
mild ketonemia. Such products are already available on the market although no reports are available on
127
the ketogenic effect of the combination of these products.
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One limitation of this study design is that the metabolic study period was only 4 hours. However, this was
129
sufficient to observe an effect on plasma ketones and FFA within the period during which peak plasma
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caffeine was observed. The half-life of caffeine is 4.5 hours, which suggests that its peak metabolic effect
131
would take place over 2-3 hours. Furthermore, the effect of each caffeine dose was only assessed once,
132
so a longer term study would be useful.
133
134
In conclusion, by enhancing lipolysis and increasing blood FFA levels, which in turn provide substrates for
135
ketogenesis, caffeine at doses of 2.5 and 5.0 mg/kg stimulated safe and mild ketonemia in healthy adults
136
to a ketone level twice that seen after an overnight fast. Several studies suggest that regular caffeine
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consumption may be linked to the decreased risk of developing late-life cognitive decline (Panza et al.
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2015). Further studies are needed to evaluate caffeine’s long term effect on ketonemia and its impact on
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brain function during aging.
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ACKNOWLEDGMENTS
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We thank our research nurses, Conrad Filteau and Christine Brodeur-Dubreuil, for their assistance in
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participant screening, blood sampling and care of the participants. SCC, CV and VSP designed the study.
144
CV, VSP, ACL, CAC and MH conducted the study. CV, VSP, CAC and SCC analyzed and interpreted the
145
data. All the authors contributed to the final article.
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REFERENCES
Acheson, K. J., Zahorska-Markiewicz, B., Pittet, P., Anantharaman, K., and Jéquier, E. 1980. Caffeine and
coffee: their influence on metabolic rate and substrate utilization in normal weight and obese individuals.
Am. J. Clin. Nutr. 33(5): 989-997.
Acheson, K. J., Gremaud, G., Meirim, I., Montigon, F., Krebs, Y., Fay, L. B., et al. 2004. Metabolic effects
of caffeine in humans: lipid oxidation or futile cycling? Am. J. Clin. Nutr. 79(1): 40-46.
Bellet, S., Kershbaum, A., and Finck, E. M. 1968. Response of free fatty acids to coffee and caffeine.
Metabolism, 17(8): 702-707. doi:10.1016/0026-0495(68)90054-1.
Bellet, S., Roman, L., DeCastro, O., Kim, K. E., and Kershbaum, A. 1969. Effect of coffee ingestion on
catecholamine release. Metabolism, 18(4): 288-291.
Butcher, R. W., Baird, C. E., and Sutherland, E. W. 1968. Effects of lipolytic and antilipolytic substances
on adenosine 3',5'-monophosphate levels in isolated fat cells. J. Biol. Chem. 243(8): 1705-1712.
Castellano, C. A., Nugent, S., Paquet, N., Tremblay, S., Bocti, C., Lacombe, G., et al. 2015. Lower brain
18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease
dementia. J. Alzheimers Dis. 43(4): 1343-1353. doi: 10.3233/JAD-141074.
Courchesne-Loyer, A., Fortier, M., Tremblay-Mercier, J., Chouinard-Watkins, R., Roy, M., Nugent, S., et
al. 2013. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans:
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Cunnane, S. C., Courchesne-Loyer, A., St-Pierre, V., Vandenberghe, C., Pierotti, T., Fortier, M., et al.
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risk and treatment of Alzheimer's disease. Ann. N. Y. Acad. Sci. 1367(1): 12-20. doi: 10.1111/nyas.12999.
Miller, D. S., Stock, M. J., and Stuart, J. A. 1974. Proceedings: The effects of caffeine and carnitine on the
oxygen consumption of fed and fasted subjects. Proc. Nutr. Soc. 33(2): 28A-29A.
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Mitchell, G. A., Kassovska-Bratinova, S., Boukaftane, Y., Robert, M. F., Wang, S. P., Ashmarina, L., et al.
1995. Medical aspects of ketone body metabolism. Clin. Invest. Med. 18(3): 193-216.
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glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol. Aging, 35(6):
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Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., and Cahill, G. F. 1967. Brain
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Table 1. Baseline demographic and biochemical parameters of the participants
148
(Mean ± SEM)
149
150
Characteristics
Age (y) 33
± 19
Men/Women 2/8
Weight (kg) 65
± 14
Height (cm) 163
± 16
Body mass index (kg/m
2
) 24
± 8
Glucose (mmol/L) 4.2
± 0.4
Lactate (mmol/L) 1.86
± 1.0
Glycated hemoglobin (%) 5.3
± 0.3
Total cholesterol (mmol/L) 4.3
± 0.8
Triacylglycerol (µmol/L) 749
± 282
Free fatty acids (µmol/L) 711
± 392
Ketones (µmol/L) 175
± 65
151
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Figure 1. Plasma caffeine concentrations during the control (CTL) metabolic study day (), after receiving
152
a 2.5 mg/kg (C-2.5) () or 5.0 mg/kg dose of caffeine (C-5.0) (). Arrow indicates breakfast. Values are
153
presented as mean ± SEM (n = 10/point); * p<0.05 CTL vs C-2.5, † p<0.05 CTL vs C-5.0, # p<0.05 C-2.5
154
vs C-5.0.
155
156
Figure 2. Plasma acetoacetate [A] and β-hydroxybutyrate [B] concentrations during the control (CTL)
157
metabolic study day (), and after receiving a 2.5 mg/kg (C-2.5) () or 5.0 mg/kg dose of caffeine (C-5.0)
158
(). Arrow indicates breakfast. The area under the curve was measured from 2 to 4-hour post-dose for
159
acetoacetate [C] and β-hydroxybutyrate [D]. Values are presented as mean ± SEM (n = 10/point);
160
* p<0.05 CTL vs C-2.5, † p<0.05 CTL vs C-5.0, # p<0.05 C-2.5 vs C-5.0.
161
162
Figure 3. Plasma free fatty acids (FFA) concentrations [A] during the control (CTL) metabolic study day
163
obtained before (), after receiving a 2.5 mg/kg dose (C-2.5) () or 5.0 mg/kg dose of caffeine (C-5.0) ().
164
Arrow indicates breakfast. The area under the curve [B] was measured from 2 to 4-hour post-dose. Values
165
are presented as mean ± SEM (n = 10/point); * p<0.05 CTL vs C-2.5, † p<0.05 CTL vs C-5.0, # p<0.05 C-
166
2.5 vs C-5.0.
167
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01234
0
2
4
6
8
10
12
14
Time (h)
Plasma caffeine [mg/L]
*
#
C-5.0C-2.5CTL
*
#
*
#
*
#
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01234
200
400
600
800
1000
Time (h)
Plasma free fatty acids [µmol/L]
*
*
A
CTL
C-2.5
C-5.0
*
#
CTL C-2.5 C-5.0
0
500
1000
1500
2000
*
#
B
Free fatty acids [µmol*h/L]
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... To address these issues, in the current study we chose to examine the effects of a BHB-salt enriched with the Renantiomer in both Keto-Naïve and Keto-Adapted individuals. The ketone salt supplement also included other potentially active ingredients including amino acids (leucine and taurine), and a modest dose of caffeine that could alone elicit an effect on performance as well as increase lipolysis and ketosis (15). In addition to measuring high-intensity exercise performance, we examined circulating concentrations of R-and S-BHB, metabolic, and hormonal responses to exercise. ...
... According to information provided by the manufacturer, the KCA supplement (KETO//OS MAX CHARGED, Pruvit Ventures, Melissa, TX) contained 8.5 g BHB salts consisting of 7.2 g BHB, 910 mg sodium, 245 mg magnesium, and 189 mg calcium. The supplement also contained 100 mg of caffeine (mean ± SD 1.3 ± 0.2 mg/kg), representing a typical dose in a serving of regular coffee that may mildly elevate ketosis (15). The supplement label also listed L-leucine and L-taurine as ingredients. ...
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Background: Acute ingestion of ketone supplements alters metabolism and potentially exercise performance. No studies to date have evaluated the impact of co-ingestion of ketone salts with caffeine and amino acids on high intensity exercise performance, and no data exists in Keto-Adapted individuals. Methods: We tested the performance and metabolic effects of a pre-workout supplement containing beta-hydroxybutyrate (BHB) salts, caffeine, and amino acids (KCA) in recreationally-active adults habitually consuming a mixed diet (Keto-Naïve; n = 12) or a ketogenic diet (Keto-Adapted; n = 12). In a randomized and balanced manner, subjects consumed either the KCA consisting of ∼7 g BHB (72% R-BHB and 28% S-BHB) with ∼100 mg of caffeine, and amino acids (leucine and taurine) or Water (control condition) 15 minutes prior to performing a staged cycle ergometer time to exhaustion test followed immediately by a 30 second Wingate test. Results: Circulating total BHB concentrations increased rapidly after KCA ingestion in KN (154 to 732 μM) and KA (848 to 1,973 μM) subjects and stayed elevated throughout recovery in both groups. Plasma S-BHB increased >20-fold 15 minutes after KCA ingestion in both groups and remained elevated throughout recovery. Compared to Water, KCA ingestion increased time to exhaustion 8.3% in Keto-Naïve and 9.8% in Keto-Adapted subjects (P < 0.001). There was no difference in power output during the Wingate test between trials. Peak lactate immediately after exercise was higher after KCA (∼14.9 vs 12.7 mM). Conclusion: These results indicate that pre-exercise ingestion of a moderate dose of R- and S-BHB salts combined with caffeine, leucine and taurine improves high-intensity exercise performance to a similar extent in both Keto-Adapted and Keto-Naïve individuals.
... Dodatkowo zwiększała się ilość wolnych kwasów tłuszczowych. W tym wypadku zbadano krótkotrwały efekt po nocnym poście [21]. L. Klosinski i wsp. ...
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Sokal A, Jarmakiewicz-Czaja S. Starzenie się mózgu i ryzyko wystąpienia zespołu otępiennego-czy odpowiednia dieta może temu zapobiec? Med Og Nauk Zdr.
... Indeed, the brain cells undergo targets constant attacks by free radicals thus requiring the most effective defense mechanism 27-29 . In line with this fact, it is substantiated that the bioavailability of chemical elements as zinc (Zn), selenium (Se), and iron (Fe), besides participating as mediators in different cell signaling processes, when acting as enzymatic co-factors has the potential of the modulating the activity of antioxidant enzymes, thereby improving the system of defense brain against ROS attack 10,28,29 . Hereupon, it is notable that studies with rodents have shown that oxidative stress in the brain can reduce the bioavailability of these minerals 30,31 . ...
Article
Amplamente consumida nos alimentos e como suplemento alimentar, a cafeína tem sido estudada devido aos seus efeitos farmacológicos, principalmente no sistema nervoso central (SNC). O presente estudo investigou se o uso crônico da cafeína pode influenciar o estado oxidativo do cérebro e a atividade comportamental de camundongos fêmeas C57BL/6. Para isso, quinze animais foram randomizados nos seguintes grupos: Controle (solução salina à 0,9%), Caf10 (10 mg / kg de cafeína) e Caf50 (50 mg / kg de cafeína). Os animais receberam uma dose diária de cafeína por via i.p. durante 120 dias. Vinte e quatro horas após a última administração, os animais foram submetidos a testes comportamentais e foram eutanasiados. O sangue foi utilizado para análises bioquímicas. No cérebro, foi avaliado o estado oxidativo e os níveis de microminerais. A cafeína não influenciou os parâmetros antropométricos, perfil lipídico e níveis de proteína Creativa. Ademais, as atividades de superóxido dismutase (SOD) e glutationa-Stransferase (GST) mantiveram o mesmo perfil de resposta. Em contrapartida, a atividade da catalase (CAT) diminuiu em ambos os grupos que receberam cafeína. Já os níveis de malondialdeído e proteína carbonilada não se alteraram entre os grupos, assim como a distribuição dos microminerais. Nenhuma dose de cafeína desencadeou comportamento do tipo ansioso nos animais. Portanto, considerando o tempo de administração da cafeína, acreditamos que houve a adaptação celular desencadeada pelo seu uso, tendendo a um efeito protetor no cérebro. Além disso, o espaço amostral reduzido foi uma limitação para entendimentos mais acurados sobre os efeitos da cafeína no SNC. Palavras-chave: Cafeína. Espécies reativas de oxigênio. Comportamento Animal.
... In 2017, Vandenberghe et al. investigated the influence of caffeine on ketogenesis. Depending on the caffeine concentration (2.5-5 mg/kg BW), an increase of ßHB in plasma of 88-116% was observed [31]. ese results are not transferable to the results reported in this study for several reasons. ...
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Background: Ketone bodies are a highly relevant topic in nutrition and medicine. The influence of medium-chain triglycerides (MCT) on ketogenesis is well known and has been successfully used in ketogenic diets for many years. Nevertheless, the effects of MCTs and coconut oil on the production of ketone bodies have only partially been investigated. Furthermore, the increased mobilisation of free fatty acids and release of catabolic hormones by caffeine suggest an influence of caffeine on ketogenesis. Methods: In a controlled, double-blind intervention study, seven young healthy subjects received 10 mL of tricaprylin (C8), tricaprin (C10), C8/C10 (50% C8, 50% C10), or coconut oil with or without 150 mg of caffeine, in 250 mL of decaffeinated coffee, over ten interventions. At baseline and after every 40 minutes, for 4 h, ßHB and glucose in capillary blood as well as caffeine in saliva were measured. Furthermore, questionnaires were used to survey sensory properties, side effects, and awareness of hunger and satiety. Results: The interventions with caffeine caused an increase in ßHB levels-in particular, the interventions with C8 highly impacted ketogenesis. The effect decreased with increased chain lengths. All interventions showed a continuous increase in hunger and diminishing satiety. Mild side effects (total = 12) occurred during the interventions. Conclusions: The present study demonstrated an influence of caffeine and MCT on ketogenesis. The addition of caffeine showed an additive effect on the ketogenic potential of MCT and coconut oil. C8 showed the highest ketogenicity.
... The effective dose and trial duration required of such a MCT ketogenic drink to optimize benefits on cognitive outcomes remains to be determined. Finally, it should be investigated whether other approaches established to produce changes in brain energy metabolism, such as caffeine (Vandenberghe et al., 2017) or exercise , should also be incorporated into such an intervention, or whether this intervention should be part of a multi-nutrient approach to mitigating neurodegenerative disease progression. ...
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The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3rd Symposium on “Nutrition for the Ageing Brain: Moving Towards Clinical Applications” held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required.
... Finally, caffeine offers an additional method that is both safe and practical for an individual to increase D-BHB levels via increased metabolic rate and free fatty acid availability (Vandenberghe et al. 2017). These findings have led to the commercial promotion of dietary supplements/products that claim to act as ketogenic beverages by adding lipids to caffeine-rich beverages such as coffee. ...
Article
Background: Ingestion of ketone supplements, caffeine and medium chain triglycerides (MCTs) may all be effective strategies to increase blood levels of the ketone body beta-hydroxybutyrate (D-BHB). However, acute ingestion of a bolus of lipids may increase oxidative stress (OS). The purpose of the study was to investigate the impact of adding varying amounts of MCTs to coffee on blood levels of D-BHB and markers of OS. Methods: Ten college-aged men ingested coffee with 0g, 28g, and 42g of MCT in a randomized order. Blood samples were collected pre, as well as two and four hours postprandial and analyzed for D-BHB, total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), glucose, triglycerides (TAG), insulin, as well as OS markers: advanced oxidation protein products (AOPP), glutathione (GSH), malondialdehyde (MDA), and hydrogen peroxide (H2O2). Results: All three treatments resulted in a significant increase in D-BHB, HDL-c, and TC, as well as a significant decrease in TAG, MDA, H2O2, and insulin. The 42g treatment was associated with significantly higher levels of AOPP and MDA. Conclusions: Acute ingestion of coffee results in favorable changes to markers of cardiometabolic health that were not impacted by the addition of 28g MCT. However, 42g MCT caused significantly greater OS.
... Coffee and caffeine consumption increased lipolysis, measured by free fatty acids and/or glycerol, peaking after 2-4 h in humans ( Flanagan et al., 2014;Mougios et al., 2003;Vandenberghe et al., 2016). It was suggested that caffeine increases lipolysis in adipose tissue by inhibiting adenosine receptor and increasing catecholamine levels via the sympathetic nervous system (Carrageta et al., 2018;Kogure et al., 2002;Wu et al., 2017). ...
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Coffee consumption is associated with reduced risk of metabolic syndrome, obesity and diabetes, which may be related to the effects of coffee and its bioactive components on lipid metabolism. Coffee contains caffeine, a known neuromodulator that acts as an adenosine receptor antagonist, as well as other components, such as chlorogenic acids, trigonelline, cafestol and kahweol. Thus, this review discusses the up-to-date knowledge of mechanisms of action of coffee and its bioactive compounds on lipid metabolism. Although there is evidence that coffee and/or its bioactive compounds regulate transcription factors (e.g. peroxisome proliferator-activated receptors and sterol regulatory element binding proteins) and enzymes (e.g. AMP-activated protein kinase) involved in lipogenesis, lipid uptake, transport, fatty acid β-oxidation and/or lipolysis, needs for the understanding of coffee and its effects on lipid metabolism in humans remain to be answered.
... If so, this would facilitate strategies to provide more ketones to fuel the aging brain by at least partially bypassing the brain glucose uptake deficit. Our overall goal was therefore to assess a potential synergistic effect of a 5-day intervention with AE and MCT on plasma ketones during a 4-h metabolic study (Courchesne-Loyer et al. 2013;Vandenberghe et al. 2017a). Hence, our primary objective was to determine whether a 5-day AE program combined with an MCT supplement would increase the plasma ketone response in older women more than either intervention alone. ...
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Objectives: Determine whether - (1) a five-day aerobic exercise (AE) program combined with a medium-chain triglyceride (MCT) supplement would increase the plasma ketone response in older women more than either intervention alone, and (2) ketonemia after these combined or separate treatments was alike in normoglycemic (NG) versus pre-diabetic (PD) women. Design: Older women (NG=10; PD=9) underwent a 4 h metabolic study after each of four different treatments: (i) no treatment control, (ii) five days of MCT alone (30 g/day), (iii) one session of 30 min of AE alone, and (iv) five days of MCT and AE combined (MCT+AE). Blood was sampled every 30 minutes over 4 h for analysis. Results: In NG, MCT+AE induced the highest AUC for plasma ketones (835 ± 341 µmol h/L), values that were 69% higher than MCT alone (P<0.05). AUCs were not different between MCT alone and MCT+AE in PD, but both treatments induced a significantly higher AUC than the control or AE alone (P<0.05). Except for a trend towards a higher ketone AUC in NG vs. PD on AE alone (P=0.091), there was no significant difference between the ketone AUCs in PD and NG. Conclusion: Combination of MCT+AE was more ketogenic in older women than MCT or AE alone. MCT+AE had a synergistic effect on ketonemia in NG but not in PD. Whether by improving insulin sensitivity with a longer term AE intervention can improve the ketogenic effect of MCT in PD and thereby increase brain ketone uptake in older people merits further investigation.
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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.
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Introduction: Medium-chain-triglycerides (MCT), formed by fatty acids with a length of 6–12 carbon atoms (C6–C12), constitute about two thirds of coconut oil (Coc). MCT have specific metabolic properties which has led them to be described as ketogenic even in the absence of carbohydrate restriction. This effect has mainly been demonstrated for caprylic acid (C8), which constitutes about 6–8% of coconut oil. Our aim was to quantify ketosis and blood glucose after intake of Coc and C8, with and without glucose intake. Sunflower oil (Suf) was used as control, expected to not break fasting ketosis, nor induce supply-driven ketosis. Method: In a 6-arm cross-over design, 15 healthy volunteers—age 65–73, 53% women—were tested once a week. After a 12-h fast, ketones were measured during 4 h after intake of coffee with cream, in combination with each of the intervention arms in a randomized order: 1. Suf (30 g); 2. C8 (20 g) + Suf (10 g); 3. C8 (20 g) + Suf (10 g) + Glucose (50 g); 4. Coc (30 g); 5. Coc (30 g) + Glucose (50 g); 6. C8 (20 g) + Coc (30 g). The primary outcome was absolute blood levels of the ketone β-hydroxybutyrate, area under the curve (AUC). ANOVA for repeated measures was performed to compare arms. Results: β-hydroxybutyrate, AUC/time (mean ± SD), for arms were 1: 0.18 ± 0.11; 2: 0.45 ± 0.19; 3: 0.28 ± 0.12; 4: 0.22 ± 0.12; 5: 0.08 ± 0.04; 6: 0.45 ± 0.20 (mmol/L). Differences were significant (all p ≤ 0.02), except for arm 2 vs. 6, and 4 vs. 1 & 3. Blood glucose was stable in arm 1, 2, 4, & 6, at levels slightly below baseline (p ≤ 0.05) at all timepoints hours 1–4 after intake. Conclusions: C8 had a higher ketogenic effect than the other components. Coc was not significantly different from Suf, or C8 with glucose. In addition, we report that a 16-h non-carbohydrate window contributed to a mild ketosis, while blood glucose remained stable. Our results suggest that time-restricted feeding regarding carbohydrates may optimize ketosis from intake of MCT. Clinical Trial Registration: The study was registered as a clinical trial on ClinicalTrials.gov, NCT03904433.
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The main purpose of this study is to examine the effect of caffeine on lipid accumulation in human hepatoma HepG2 cells. Significant decreases in the accumulation of hepatic lipids, such as triglyceride (TG), and cholesterol were observed when HepG2 cells were treated with caffeine as indicated. Caffeine decreased the mRNA level of lipogenesis-associated genes (SREBP1c, SREBP2, FAS, SCD1, HMGR and LDLR). In contrast, mRNA level of CD36, which is responsible for lipid uptake and catabolism, was increased. Next, the effect of caffeine on AMP-activated protein kinase (AMPK) signaling pathway was examined. Phosphorylation of AMPK and acetyl-CoA carboxylase were evidently increased when the cells were treated with caffeine as indicated for 24 h. These effects were all reversed in the presence of compound C, an AMPK inhibitor. In summary, these data indicate that caffeine effectively depleted TG and cholesterol levels by inhibition of lipogenesis and stimulation of lipolysis through modulating AMPK-SREBP signaling pathways. [BMB Reports 2013; 46(4): 207-212].
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Studies in carriers of mutations that cause early-onset familial Alzheimer’s disease (eoFAD) are of significant interest.We showed previously that regional glucose hypometabolism could be detected many years before disease onset in presenilin 1(PSEN1) mutation carriers. Here we studied four members of a family with a Met146Val PSEN1 mutation, two symptomatic carriers and two non-carriers, longitudinally with 18F-FDG PET over a period of about two and four years, respectively. The two mutation carriers showed global cortical glucose hypometabolism over time with the most distinct decline occurring in the posterior cingulate, the parietal and parietotemporal cortex, which was also observed when compared with a group of 23 healthy controls and a group of 27 sporadic Alzheimer’s disease (sAD) patients. This decline correlated with cognitive deterioration overtime as measured by neuropsychological tests. Postmortem examination of brain tissue revealed substantially elevated levels of AD type neuropathology in terms of neuritic plaques and neurofibrillary tangles in the two mutation carriers compared with a reference group of 249 sAD patients. In the mutation carriers, the amount of neuritic plaques but not neurofibrillary tangles correlated hereby significantly with regional glucose metabolism as measured by 18F-FDG on the last scanning occasions, which were performed four and approximately five years before death, respectively. We here show that FDG PET can depict in vivo the aggressive disease progression in eoFAD mutation carriers in relationship to neuropathology.
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The actions of certain lipolytic and antilipolytic agents were studied in isolated fat cells at the level of cyclic AMP. The following observations were made. Epinephrine (5.5 µM) produced small but significant changes in cyclic AMP levels in 10-min incubations while caffeine (1 mM) was without significant effect. In combination, epinephrine and caffeine acted synergistically, producing large increases in cyclic AMP, indicating that, as in other systems, the catecholamines act to stimulate adenyl cyclase and the methyl xanthines act to inhibit the cyclic nucleotide phosphodiesterase. Other hormones which acted to increase cyclic AMP levels in the presence of 1 mM caffeine included adrenocorticotropic hormone (ACTH), glucagon, thyroid-stimulating hormone, luteinizing hormone, norepinephrine, and the synthetic catecholamine isoproterenol. Increased levels of cyclic AMP were detectable within 30 sec after the addition of epinephrine to fat cells incubated with 1 mM caffeine and were maximal at about 6 min, after which they declined. Supramaximal epinephrine and supramaximal ACTH together did not produce greater stimulation than either agent alone, which suggested that they might act at the same location. Three compounds with antilipolytic activity were tested. Insulin decreased cyclic AMP levels in fat cells exposed to epinephrine, ACTH, or glucagon in the presence of caffeine, while the β-adrenergic blocking agent pronethalol was effective against epinephrine but not ACTH or glucagon under the experimental conditions used. Nicotinic acid decreased cyclic AMP levels in the presence of epinephrine.
Article
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.
Article
Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments. Copyright © 2014 Elsevier Ltd. All rights reserved.
Article
A prolonged preclinical phase of more than two decades before the onset of dementia suggested that initial brain changes of Alzheimer’s disease (AD) and the symptoms of advanced AD may represent a unique continuum. Given the very limited therapeutic value of drugs currently used in the treatment of AD and dementia, preventing or postponing the onset of AD and delaying or slowing its progression are becoming mandatory. Among possible reversible risk factors of dementia and AD, vascular, metabolic, and lifestyle-related factors were associated with the development of dementia and late-life cognitive disorders, opening new avenues for the prevention of these diseases. Among diet-associated factors, coffee is regularly consumed by millions of people around the world and owing to its caffeine content, it is the best known psychoactive stimulant resulting in heightened alertness and arousal and improvement of cognitive performance. Besides its short-term effect, some case-control and cross-sectional and longitudinal population-based studies evaluated the long-term effects on brain function and provided some evidence that coffee, tea, and caffeine consumption or higher plasma caffeine levels may be protective against cognitive impairment/decline and dementia. In particular, several cross-sectional and longitudinal population-based studies suggested a protective effect of coffee, tea, and caffeine use against late-life cognitive impairment/decline, although the association was not found in all cognitive domains investigated and there was a lack of a distinct dose-response association, with a stronger effect among women than men. The findings on the association of coffee, tea, and caffeine consumption or plasma caffeine levels with incident mild cognitive impairment and its progression to dementia were too limited to draw any conclusion. Furthermore, for dementia and AD prevention, some studies with baseline examination in midlife pointed to a lack of association, although other case-control and longitudinal population-based studies with briefer follow-up periods supported favourable effects of coffee, tea, and caffeine consumption against AD. Larger studies with longer follow-up periods should be encouraged, addressing other potential bias and confounding sources, so hopefully opening new ways for diet-related prevention of dementia and AD.
Article
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.
Article
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.
Article
The effect of coffee, decaffeinated coffee and a control beverage on plasma FFA was studied in a group of normal human subjects. The effect of caffeine sodium benzoate was also studied in the dog. Significant elevations in FFA were observed after coffee and caffeine which usually reached their peak in 3 or 4 hours. The administration of sucrose significantly reduced the immediate FFA response. The FFA effects with decaffeinated coffee were markedly less than with regular coffee and were similar to that of the control beverage. These effects are considered to be of importance, particularly in that they may be related to other disturbances in lipid metabolism.