5D Library › Fasting, Ketones and the Metabolic Basis of Attention · 中文
Chapter 3. Ketones and the Brain: β-Hydroxybutyrate as Fuel and Signal
Through the barrier
The brain is walled off from the blood by the blood–brain barrier, a layer of tightly joined cells lining its capillaries. Glucose crosses it on a dedicated transporter. Ketone bodies cross on another family, the monocarboxylate transporters (MCTs), which also carry lactate and pyruvate.
Evidence
MCT1 is found in the endothelial cells of the blood–brain barrier and in astrocytes, and MCT2 in neurons; their amount in the barrier rises during fasting and on a ketogenic diet, and is higher in suckling animals, whose milk-based diet keeps them mildly ketotic (Pierre and Pellerin 2005). Because transport depends on concentration, the brain’s uptake of ketones rises with their level in the blood. Positron emission tomography studies in humans show brain ketone uptake rising roughly in proportion to blood ketones across the range reached by diet and fasting (Cunnane et al. 2020).
Once inside a neuron, β-hydroxybutyrate is oxidised to acetoacetate, which is activated to acetoacetyl-CoA and split into two molecules of acetyl-CoA. These enter the citric acid cycle exactly as acetyl-CoA from glucose does. From that point on, the brain cannot tell which fuel it came from.
How much of the brain’s fuel?
Chapter 1 reported Owen’s finding that after five to six weeks of fasting ketones supplied about 60 per cent of the brain’s oxygen consumption. The levels reached in everyday schedules are far lower.
Calculation
A simple saturating model of the brain’s ketone share, , with mM chosen so that the model gives about 60 per cent at 5 mM, roughly the situation in Owen’s prolonged fast. The blood levels are typical values for each situation, not measurements from one person.
K_half = 3.3 # mM at which ketones would cover half of the brain's fuel (assumed)
def ketone_share(bhb_mM):
return bhb_mM / (bhb_mM + K_half)
print("blood BHB (mM) situation share of brain fuel (model)")
for bhb, what in ((0.1, "after a normal meal"), (0.3, "overnight fast"), (0.5, "16:8, end of the fast"),
(1.0, "about 1-2 days without food"), (2.0, "about 3 days"), (5.0, "weeks of fasting")):
print(f"{bhb:14.1f} {what:32s} {ketone_share(bhb):6.0%}")
# blood BHB (mM) situation share of brain fuel (model)
# 0.1 after a normal meal 3%
# 0.3 overnight fast 8%
# 0.5 16:8, end of the fast 13%
# 1.0 about 1-2 days without food 23%
# 2.0 about 3 days 38%
# 5.0 weeks of fasting 60%
The model is crude, and the real relation varies between people and with how long the body has been adapted to ketones. But the order of magnitude is the point: at the 0.2–0.5 mM typical at the end of a 16-hour fast, ketones supply perhaps a tenth of the brain’s fuel; the rest is still glucose. The brain of a person on a 16:8 schedule is not “running on ketones”. Any effect of such a schedule on attention, if there is one, is unlikely to come from a change of fuel alone.
A molecule with a second job
Since about 2010, β-hydroxybutyrate has been studied less as a fuel and more as a signal.
Evidence
Tadahiro Shimazu, Eric Verdin and colleagues reported that β-hydroxybutyrate inhibits class I histone deacetylases at concentrations of 1–2 mM in cultured cells, increasing the acetylation of histones and the expression of genes that protect against oxidative stress, FOXO3A and MT2; fasting and calorie restriction had similar effects in mouse kidney (Shimazu et al. 2013). Yun-Hee Youm, Vishwa Dixit and colleagues reported that β-hydroxybutyrate suppresses the NLRP3 inflammasome, an inflammatory signalling complex, in mouse and human immune cells (Youm et al. 2015). John Newman and Verdin reviewed these and other signalling roles (Newman and Verdin 2014).
Evidence
Not every finding has held up in every system. Sabrina Chriett and colleagues compared β-hydroxybutyrate with butyrate, a related molecule, in several cell types and found that butyrate was a strong histone deacetylase inhibitor while β-hydroxybutyrate, at comparable concentrations, had little such effect (Chriett et al. 2019).
Two cautions follow. First, most signalling effects were found at 1–2 mM or more, levels reached after a day or two of fasting, not at the end of a 16-hour window. Second, cell and mouse studies show what β-hydroxybutyrate can do; whether it does so in human brains at everyday levels is a separate question. The best current summary is that ketones are both fuel and signal, that the signalling is real in the laboratory, and that its importance in people is not yet known (Puchalska and Crawford 2017).
Hunger, alertness and the brain’s other signals
If fuel and β-hydroxybutyrate signalling are too weak at 16 hours to explain how people feel, what else changes? Several things, and none of them is simple.
Hunger itself is an alerting signal. In animals, hunger increases exploratory activity and the drive to forage, and the hormones of fasting, such as ghrelin and the falling level of insulin, act on brain regions involved in arousal and reward. Mark Mattson and colleagues have argued that the switch between fed and fasted states, repeated day after day, is itself what benefits the brain, through these and other signals (Mattson et al. 2018). That argument rests mainly on animal work.
Evidence
A systematic review of experimental studies of fasting and cognition in humans found mixed results: some studies reported impaired performance on some tasks, such as complex attention and mental flexibility, after fasts of a day or more, others found no change, and few studies were large (Benau et al. 2014). A later review of intermittent fasting and cognitive function concluded that animal studies are broadly positive but that human evidence is scarce and inconsistent (Gudden et al. 2021).
Hypothesis · not established
Not established. Any change in attention on a 16:8 schedule, in healthy adults, is more likely to come from hunger signals, meal timing and changes in sleep and routine than from ketones as fuel. The hypothesis predicts that, in Chapter 9’s trial, differences in attention between schedules will not be explained by morning β-hydroxybutyrate levels. It would be refuted if, within the 16:8 period, days with higher β-hydroxybutyrate consistently showed better attention after accounting for sleep.
References
Fan, Y. (2026). Fasting, Ketones and the Metabolic Basis of Attention: Autophagy, β-Hydroxybutyrate and the Bioenergetics of Intermittent Fasting [断食、酮体与注意力的代谢基础] (Version 1.0.0). 5D Library. https://doi.org/10.5281/zenodo.23684203 · Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0).